Supporting Information

Out of the abyss: Genome and metagenome mining reveals unexpected environmental distribution of abyssomicins

Alba Iglesias1, Adriel Latorre‐Pérez2, James E. M. Stach3, Manuel Porcar2,4, Javier Pascual2

1 School of Biology, Devonshire Building, Newcastle University, Newcastle, United Kingdom.

2 Darwin Bioprospecting Excellence SL, Paterna, Spain.

3 School of Biology, Ridley Building, Newcastle University, Newcastle, United Kingdom; Centre for Synthetic Biology and the Bioeconomy, Baddiley-Clark Building, Newcastle University, Newcastle, United Kingdom.

4 Institute for Integrative Systems Biology (I2SysBio), University of Valencia-CSIC, Paterna, Spain.

Corresponding author: [email protected]

Contents Page Figure S1. Habitat distribution of the metagenomes analysed for the presence of AbyU, AbmU and AbsU. 2 Figure S2. Taxonomic profile at the phylum level of ten marine (1-10), ten terrestrial (11-20) and ten Diels- Alderase positive (21-30) metagenomes. These metagenomes were randomly selected from the 3027 metagenomes analysed. The ten Diels-Alderase positive were six terrestrial (21-26), one 3 Arthropoda-associated (27) and three plant-associated (28-30). Only the most abundant phyla are shown. Numbers above each bar plot indicate metagenome size (Mb). Figure S3. Taxonomic profile at the order level of ten marine (1-10), ten terrestrial (11-20) and ten Diels- Alderase positive (21-30) metagenomes. These metagenomes were randomly selected from the 4 3027 metagenomes analysed. The ten Diels-Alderase positive were six terrestrial (21-26), one Arthropoda-associated (27) and three plant-associated (28-30). Figure S4. Habitat distribution of the Diels-Alderase positive isolates found by genome mining. 5 Figure S5. Habitat distribution of the Diels-Alderase positive isolates found by genome mining to have an 6 abyssomicin or potential abyssomicin BGC (both total and partial). Figure S6. Habitat distribution of the Diels-Alderase positive isolates found by genome mining that do not 7 harbour any abyssomicin nor potential abyssomicin BGC. Figure S7. Abyssomicin and potential abyssomicin BGCs recovered from genome mining classified as clusters 8 type 1a and 1b. Figure S8. Abyssomicin and potential abyssomicin BGCs recovered from genome mining classified as clusters 9 type 2a and 2b. Figure S9. Abyssomicin and potential abyssomicin BGCs recovered from genome mining classified as clusters 10 type 3 and 4. Figure S10. Abyssomicin and potential abyssomicin BGCs recovered from genome mining classified as clusters 11 type 5. Figure S11. Potential tetronomycin BGC in S. olindensis, potential chlorothricin BGC from A. wychmicini and A. 12 pelletieri and quartromycin BGCs from A. albispora and A. orientalis. Table S1. Abyssomicin producing bacteria as reported in literature. 13 Table S2. Isolation details of the abyssomicin producers isolated from aquatic environments. 14 Table S3. Nucleotide and protein sequences of the Diels Alderase proteins present in aby, abs and abm 15 BGCs. Table S4. Identity percentage at protein (above) and nucleotide (below) level between the Diels Alderase 16 proteins present in aby, abs and abm BGCs. Table S5. Classification of metagenomic samples from aquatic environments mined for AbyU, AbsU and 17 AbmU. Numbers represent Diels-Alderase positive/mined metagenomes. Table S6. Classification of metagenomic samples from terrestrial environments mined for AbyU, AbsU and 18 AbmU. Numbers represent Diels-Alderase positive/mined metagenomes. Table S7. Classification of metagenomic samples from engineered environments mined for AbyU, AbsU and 19 AbmU. Numbers represent Diels-Alderase positive/mined metagenomes. Table S8. Classification of metagenomic samples from host-associated environments mined for AbyU, AbsU 20-21 and AbmU. Numbers represent Diels-Alderase positive/mined metagenomes. Table S9. Proteins within the non-redundant sequence database (NCBI) with significative alignments to AbyU, AbmU, AbsU and VASRM7_509. Columns displaying the Diels-Alderase homologs show 22-25 protein ID, alignment E-value and similarity percentage. Table S10. The abyssomicin biosynthetic gene cluster from M. maris AB-16-032 (modified from Gottardi et al., 26 2011). Table S11. The abyssomicin biosynthetic gene cluster from S. koyangensis SCSIO 5802 (modified from Song 27-28 et al., 2017). Table S12. The abyssomicin biosynthetic gene cluster from Streptomyces sp. LC-6-2 (adapted from Wang et 29-30 al., 2017). Table S13. The abyssomicin biosynthetic gene cluster from Verrucosispora sp. MS100047 (KF826681.1). 31 Table S14-S84. Recovered BGCs and ORFs surrounding AbyU homologs. 32-140 Table S85-S100. Predicted genomic islands. 141-171 References 172

1 Figure S1. Habitat distribution of the metagenomes analysed for the presence of AbyU, AbmU and AbsU.

2 Figure S2. Taxonomic profile at the phylum level of ten marine (1-10), ten terrestrial (11-20) and ten Diels-Alderase positive (21-30) metagenomes. These metagenomes were randomly selected from the 3027 metagenomes analysed. The ten Diels-Alderase positive were six terrestrial (21-26), one Arthropoda-associated (27) and three plant-associated (28-30). Only the most abundant phyla are shown. Numbers above each bar plot indicate metagenome size (Mb).

3 Figure S3. Taxonomic profile at the order level of ten marine (1-10), ten terrestrial (11-20) and ten Diels-Alderase positive (21-30) metagenomes. These metagenomes were randomly selected from the 3027 metagenomes analysed. The ten Diels-Alderase positive were six terrestrial (21-26), one Arthropoda-associated (27) and three plant-associated (28-30).

4 Figure S4. Habitat distribution of the Diels-Alderase positive isolates found by genome mining.

5 Figure S5. Habitat distribution of the Diels-Alderase positive isolates found by genome mining to have an abyssomicin or potential abyssomicin BGC (both total and partial).

6 Figure S6. Habitat distribution of the Diels-Alderase positive isolates found by genome mining that do not harbour any abyssomicin nor potential abyssomicin BGC.

7 Figure S7. Abyssomicin and potential abyssomicin BGCs recovered from genome mining classified as clusters type 1a and 1b. Gene names in black are common to aby, abs and abm BGCs. Blue font represents genes present only in M. maris AB-18-032, grey font represents genes present only in Streptomyces sp. LC-6-2 and light blue font represent genes unique to S. koyangensis SCSIO 5802. In maroon font appear those genes that appear both in aby and abs BGCs, in light brown those genes that appear both in aby and abm BGCs and in yellow those genes that appear both in abs and abm BGCs. Grey boxes indicate the conserved regions shared between the type 1 clusters. Dotted lines indicate genetic islands.

8 Figure S8. Abyssomicin and potential abyssomicin BGCs recovered from genome mining classified as clusters type 2a and 2b. Gene names in black are common to aby, abs and abm BGCs. Blue font represents genes present only in M. maris AB-18-032, grey font represents genes present only in Streptomyces sp. LC-6-2 and light blue font represent genes unique to S. koyangensis SCSIO 5802. In maroon font appear those genes that appear both in aby and abs BGCs, in light brown those genes that appear both in aby and abm BGCs and in yellow those genes that appear both in abs and abm BGCs. Grey boxes indicate the conserved regions shared between the type 2 clusters. Dotted lines indicate genetic islands.

9 Figure S9. Abyssomicin and potential abyssomicin BGCs recovered from genome mining classified as clusters type 3 and 4. Gene names in black are common to aby, abs and abm BGCs. Gene names in black are common to aby, abs and abm BGCs. Blue font represents genes present only in M. maris AB-18-032, grey font represents genes present only in Streptomyces sp. LC-6-2 and light blue font represent genes unique to S. koyangensis SCSIO 5802. In maroon font appear those genes that appear both in aby and abs BGCs, in light brown those genes that appear both in aby and abm BGCs and in yellow those genes that appear both in abs and abm BGCs. Grey boxes indicate the conserved regions shared between the type 3 and type 4 clusters. Dotted lines indicate genetic islands.

10 Figure S10. Abyssomicin and potential abyssomicin BGCs recovered from genome mining classified as clusters type 5. Gene names in black are common to aby, abs and abm BGCs. Blue font represents genes present only in M. maris AB-18-032, grey font represents genes present only in Streptomyces sp. LC-6-2 and light blue font represent genes unique to S. koyangensis SCSIO 5802. In maroon font appear those genes that appear both in aby and abs BGCs, in light brown those genes that appear both in aby and abm BGCs and in yellow those genes that appear both in abs and abm BGCs.

11 Figure S11. Potential tetronomycin BGC in S. olindensis DAUFPE 5622, potential chlorothricin BGC from A. wychmicini DSM 45934 and A. pelletieri DSM 43383 and quartromycin BGCs from A. albispora WP1 and A. orientalis Q427-8. The Diels-Alderase homologs are displayed in blue. Dotted lines indicate genetic islands.

12 Table S1. Abyssomicin producing bacteria as reported in literature.

Microorganism Isolation location Habitat Reference Accession Abyssomicin structure Sediment Sea of Japan Micromonospora maris AB-18-032 Aquatic (Riedlinger et al., 2004) JF752342 B, C, atrop-C, D, G, H (-289 m) Soil Ile de Paradis Streptomyces sp. HKI0381 Terrestrial (Niu et al., 2007) - E (Senegal) Rock soil Campeche Streptomyces sp. CHI39 Terrestrial (Igarashi et al., 2010) - I (Mexico) Forest soil Kaiserslautern Streptomyces sp. Ank 210 Terrestrial (Abdalla et al., 2011) - ent-homoA, ent-homoB (Germany) South China Sea deep- Verrucosispora sp. MS100128 Aquatic (Wang et al., 2013) - B, C, atrop-C, D, H, J, K, L sea sediment (−2733 m) Streptomyces sp. RLUS1487 Marine Aquatic (León et al., 2015) - 2, 3, 4, 5 South China Sea Verrucosispora sp. MS100047 Aquatic (Huang et al., 2016) KF826681 B sediment Soil Lotts Creek coal fire Streptomyces sp. LC-6-2 Terrestrial (Wang et al., 2017) KY432814 M, N, O, P, Q, R, S, T, U, V, W, X (United States) South China Sea 2, 4, neo-A, neo-B, neo-C, neo-D, Streptomyces koyangensis SCSIO 5802 Aquatic (Song et al., 2017) MG243704 sediment (−3536 m) neo-E, neo-F, neo-G, neo-2

13 Table S2. Isolation details of the abyssomicin producers isolated from aquatic environments.

Microorganism Isolation details Reference Isolated on a colloidal chitin agar plate which had been inoculated with a suspension Micromonospora maris AB-18-032 of a sediment sample collected from the Sea of Japan and incubated at 30°C for 4 (Riedlinger et al., 2004) weeks. Isolated using oatmeal agar from a sediment sample collected from the South China Verrucosispora sp. MS100128 (Wang et al., 2013) Sea at 2733 m below sea level. Isolated on AIS medium from a marine sediment sample collected by SCUBA near Streptomyces sp. RLUS1487 (León et al., 2015) American Samoa. Isolated on a VER01 agar plate from a sediment sample collected in the South China Verrucosispora sp. MS100047 (Huang et al., 2016) Sea at 28 °C. Isolated from a sediment sample collected from the South China Sea at a depth of Streptomyces koyangensis SCSIO 5802 (Song et al., 2017) -3536 m.

14 Table S3. Nucleotide and protein sequences of the Diels Alderase proteins present in aby, abs and abm BGCs.

Gene/Protein Sequence abyU atgactgagcgactggagacgcgaccgcaggccctgctcatcaaggtgcccaccgagatcgtggtgaaggtggtcgacgacgtggacgtggccg ctccggcggtggggcaggtgggcaaattcgacgacgagttgtacgacgaggccggtgcccagatcggcacgtccagcggcaacttccgcatcga gtacgtgcgaccgaccgacggcggactgctcacctactaccaggaggacatcactctctccgatggggtgatccacgcggagggctgggcggact tcaacgacgtgcggacgagtaagtgggtgttctacccggcgaccggggtgagcggccgctacctgggcctcaccggcttccggcagtggcggatg acgggcgtgcgcaagtccgccgaggcgcggatcctgctcggcgagtga abmU atgaacgaacgcttcaccctgcccgcccacagccccgccctcgcggcgctcgtccccgagttcctcgacctggcgcgagccgcgagcggcgatcc ggccgccgaggagcgcgacctcgcggtctgggagaacctcacggaacacgtctcgctggactaccggttcgccaacccgcccgtgcacggtccc ggcgactgggacacgtacgacagccgcttcgtggaccccgccggcgtggagatcggcaccctccagggcaccggacgcatcctgtacgagcgtt cgtcggacgcgcacctgatgatgtactaccgcgagcagctgaccttccccgacgggacggcccagaccgcgggctgggtcgacggcaccgcgat cctcggcggggcctggcagcgcttccccatcctggggtcgggcggccggtacggctccatgatcgggctgcgctccttccagcccacccccgaggc gccgcacagcctctaccgcacccacctggtgctccgggagatccccggcgggcacgggctgaccgaccccgaggagatcgacgcggcactgtc gctgctcggcgccttcgtgggcccctcggtcaacccggcgaccggcaacggccgcctcgaaccccccgtacgcgccgggcgcaccgcctga absU gtggtgttgcaggtcctgtccgactggctcacgccgctggtcgcgacgcccccgaagaccgtctcgccggaggtcggcgccctcaaggacacggg caggtcgctcatcctgcgcgacctgagggagaaggtggtcgcctacgagtcgaacaaccccgaccccaccggcaccacccccaccgagaacg acttcgccacggtccggctggagatcttcggccccgacggtacgcagatcgggaccaccgagggcgccgggcggatgctgtaccggcaggaga aggacgagcacttcatcgcctacttcggcgaggagatcacgctcaacgacggcaacgtcatccgcgcgggcgggctcgtggacgacgcgcggct gacggcgggcgaacacgccacgttccccgcggtggtggtcagcgggccgctgcgcggcgcgatcggcttccgccagttccggccgctggtcaag gagtcgcacacgacgtacgagtcctcgatcgtcgtctaccggaggtga AbyU MTERLETRPQALLIKVPTEIVVKVVDDVDVAAPAVGQVGKFDDELYDEAGAQIGTSSGNFRIEYVRPTDGG LLTYYQEDITLSDGVIHAEGWADFNDVRTSKWVFYPATGVSGRYLGLTGFRQWRMTGVRKSAEARILLGE AbmU MNERFTLPAHSPALAALVPEFLDLARAASGDPAAEERDLAVWENLTEHVSLDYRFANPPVHGPGDWDTYD SRFVDPAGVEIGTLQGTGRILYERSSDAHLMMYYREQLTFPDGTAQTAGWVDGTAILGGAWQRFPILGSG GRYGSMIGLRSFQPTPEAPHSLYRTHLVLREIPGGHGLTDPEEIDAALSLLGAFVGPSVNPATGNGRLEPP VRAGRTA AbsU MVLQVLSDWLTPLVATPPKTVSPEVGALKDTGRSLILRDLREKVVAYESNNPDPTGTTPTENDFATVRLEIF GPDGTQIGTTEGAGRMLYRQEKDEHFIAYFGEEITLNDGNVIRAGGLVDDARLTAGEHATFPAVVVSGPLR GAIGFRQFRPLVKESHTTYESSIVVYRR

15 Table S4. Identity percentage at protein (above) and nucleotide (below) level between the Diels Alderase proteins present in aby, abs and abm BGCs.

AbyU AbmU AbsU 37% 31% AbyU * 56% 55% 37% 30% AbmU * 56% 57% 31% 30% AbsU * 55% 57%

16 Table S5. Classification of metagenomic samples from aquatic environments mined for AbyU, AbsU and AbmU. Numbers represent Diels-Alderase positive/mined metagenomes.

Unchlorinated 0/9 Drinking water Unclassified 0/8 Acid Mine Drainage 0/7 Cave water 0/11 Ground water Contaminated 0/14 Mine drainage 0/4 Unclassified 0/71 Epilimnion 0/25 Hypolimnion 0/8 Lentic Littoral zone 0/2 Sediment 0/15 Unclassified 0/60 Freshwater Sediment 0/9 Lotic Unclassified 0/12 Sediment 0/12 Pond Unclassified 0/7 River Unclassified 0/39 Sediment Unclassified 0/41 Unclassified Unclassified 0/18 Environmental Aquatic Glacial Lake 0/19 Ice Glacier 0/9 Ice accretions 0/1 Lake Sediment 0/46 Wetlands Bog 0/25 Coastal Sediment 0/25 Estuary 0/25 Salt marsh 0/19 Intertidal zone Sediment 0/10 Marine Unclassified 0/40 Abyssal plane 0/3 Aphotic zone 0/22 Oceanic Sediment 0/57 Unclassified 0/94 Sediment 0/10 Alkaline Unclassified 0/7 Hypersaline Microbial mats 0/6 Non-marine Saline and Alkaline Epilimnion 0/1 Saline Sediment 0/4 Unclassified 0/20

17 Table S6. Classification of metagenomic samples from terrestrial environments mined for AbyU, AbsU and AbmU. Numbers represent Diels-Alderase positive/mined metagenomes.

Crop Agricultural land 0/17 Agricultural soil 18/57 Forest Soil 0/26 Loam Grasslands 2/42 Unclassified 0/8 Oil-contaminated 0/8 Clay Unclassified 1/18 Fossil Unclassified 0/1 Hot Acidic 0/4 Desert 1/36 Sand Oil contaminated 0/2 Soil Unclassified 1/19 Agricultural 7/18 Agricultural land 0/84 Environmental Terrestrial Desert 0/20 Forest Soil 5/233 Unclassified Grasslands 1/32 Permafrost 0/45 Shrubland 0/1 Tropical rainforest 0/17 Permafrost 0/12 Wetlands Unclassified 0/50 Mine Unclassified 0/4 Geologic Sediment Unclassified 0/16 Plant litter Unclassified Unclassified 8/130 Rock-dwelling (endoliths) Unclassified Unclassified 0/18 Rock-dwelling (subaerial biofilms) Unclassified Unclassified 0/8 Volcanic Fumaroles Unclassified 0/9

18 Table S7. Classification of metagenomic samples from engineered environments mined for AbyU, AbsU and AbmU. Numbers represent Diels-Alderase positive/mined metagenomes.

City Subway Unclassified 0/34 Built environment Solar panel Unclassified Unclassified 0/3 Unclassified Unclassified Unclassified 0/4 Bioreactor 0/11 Grass Unclassified 0/1 Composting Unclassified Unclassified 0/23 Solid waste Wood Bioreactor 0/4 Landfield Unclassified Unclassified 0/3 Solid Animal Waste Unclassified Unclassified 0/6 Aerobic Unclassified Unclassified 6/6 Marine intertidal flat sediment Engineered Unclassified 0/2 Bioreactor Continuous culture inoculum Marine sediment inoculum Unclassified 0/11 Unclassified Unclassified Unclassified 0/17 Microbial solubilization Unclassified Unclassified 0/4 of coal Biotransformation Mixed alcohol Unclassified Unclassified 0/2 bioreactor Activated Sludge Unclassified Unclassified 0/21 Anaerobic digestor Unclassified Unclassified 0/20 Waste water Mine water Unclassified 0/2 Industrial waste water Petrochemical Unclassified 0/14 Unclassified Unclassified 0/13

19 Table S8. Classification of metagenomic samples from host-associated environments mined for AbyU, AbsU and AbmU. Numbers represent Diels-Alderase positive/mined metagenomes.

Host- Green algae Ectosymbionts Unclassified 0/11 associated Algae Red algae Ectosymbionts Unclassified 0/15 Digestive system Fecal Unclassified 0/18 Animal Skin Unclassified Unclassified 0/1 Cuticle Epibionts 0/1 Integument Unclassified Unclassified 0/8 Annelida Intracellular endosymbiont Trophosome Unclassified 0/2 Reproductive system Egg capsule Unclassified 0/2 Unclassified Unclassified Unclassified 0/1 Ant dump Unclassified Unclassified 0/11 Foregut Unclassified 0/1 P3 segment 0/1 Digestive system Gut Proctodeal segment 0/1 Unclassified 1/40 Midgut Unclassified 0/4 Secondary Unclassified 0/1 Arthropoda Intracellular endosymbiont Unclassified Unclassified 1/1 Fungus gallery Unclassified 0/1 Symbiotic fungal gardens and Garden dump 0/1 Fungus garden galleries Unclassified 1/9 Unclassified Unclassified 0/6 Tissue Unclassified Unclassified 0/15 Unclassified Unclassified Unclassified 1/3 Ceca Lumen 0/1 Birds Digestive system Crop Lumen 0/9 Cnidaria Unclassified Unclassified Unclassified 0/33 Digestive system Unclassified Unclassified 0/1 Fish Skin Epidermal mucus Unclassified 0/3 Mycelium Unclassified Unclassified 0/41 Fungi Unclassified Unclassified Unclassified 0/11 Insecta Digestive system Unclassified Unclassified 0/14 Invertebrates Cnidaria Coral Unclassified 0/15 Fecal unclassified 0/17 Rumen 0/18 Foregut Digestive system Unclassified 0/12 Mammals Rumen 0/6 Stomach Unclassified 0/2 Nervous system Brain Unclassified 0/11 Tissue Unclassified Unclassified 0/8 Bacteria Unclassified Unclassified 0/8 Microbial Endosymbionts Unclassified 0/2 Dinoflagellates Unclassified Unclassified 0/7 Digestive system Ceca Uncharacterized 0/1 Mollusca Respiratory system Gills Extracellular 0/7 Shell Unclassified Unclassified 0/2 Plants Endosphere Unclassified Unclassified 1/11 Leaf Unclassified Unclassified 0/5 Nodule Unclassified Unclassified 0/4 Peat moss Unclassified Unclassified 0/14 Epiphytes Unclassified 5/32 Phylloplane Unclassified Unclassified 0/27 Phyllosphere Unclassified Unclassified 4/57 Rhizoplane Endophytes Unclassified 0/1

20 Epiphytes Unclassified 19/106 Soil Unclassified 2/2 Unclassified Unclassified 1/54 Epiphytes Unclassified 0/2 Rhizosphere Soil Unclassified 11/116 Unclassified Unclassified 41/157 Nodule Unclassified 0/2 Roots Unclassified Unclassified 12/58 Wood Unclassified Unclassified 0/16 Porifera Unclassified Unclassified Unclassified 0/19 Ascidians Unclassified Unclassified 0/9 Tunicates Unclassified Unclassified Unclassified 0/1

21 Table S9. Proteins within the non-redundant sequence database (NCBI) with significative alignments to AbyU, AbmU, AbsU and VASRM7_509. Columns displaying the Diels-Alderase homologs show protein ID, alignment E-value and similarity percentage.

Genome accession, Microorganism AbyU homolog AbsU homolog AbmU homolog number of contigs, Protein location sequencing technology WP_104480634.1 (5e- 31/44.62%) WP_104480633.1 (4e- WP_104476817.1 (4e- WP_104476817.1 (9e- NZ_PTIX00000000.1, Actinokineospora auranticolor YU 961-1 2 Abyssomicin BGCs, total 11/33.68%) 62/70.99%) 11/34.44%) 61 contigs, Illumina HiSeq WP_104476817.1 (2e- 07/38.67%) WP_131902816.1 (1e- WP_131902816.1 (9e- WP_131902816.1 (2e- SMKU00000000.1, Actinomadura sp. H3C3 Not enough data 07/30.97%) 09/27.34%) 10/31.90%) 805 contigs, Illumina HiSeq NZ_CP015163.1, WP_113696543.1 (1e- WP_113696543.1 (2e- WP_113696543.1 (8e- Amycolatopsis albispora WP1 Complete genome, PacBio Quartromicin BGC, partial 13/38.10%) 06/32.38%) 11/30.67%) RSII AXK36488.1 (4e- AXK36488.1 (4e- AXK36488.1 (6e- CP031320.1, Streptomyces armeniacus ATCC 15676 Not a BGC 13/34.88%) 08/32.58%) 12/28.23%) 21 contigs, Illumina MiSeq WP_103337399.1 (4e- WP_103337399.1 (5e- NZ_PPHF00000000.1, Amycolatopsis sp. CA-126428 No hit Not enough data 16/36.19%) 12/37.37%) 188 contigs, Illumina HiSeq Streptomyces caatingaensis CMAA WP_049718340.1 (4e- WP_049718340.1 (1e- WP_049718340.1 (5e- NZ_LFXA00000000.1, Not a BGC 1322 20/40.37%) 11/36.17%) 30/38.41%) 18 contigs, PacBio WP_014140910.1 (3e- WP_014140910.1 (2e- WP_014140910.1 (4e- NC_017586.1, Streptomyces cattleya DSM 46488 Potential BGC 21/34.55%) 14/36.90%) 14/34.31%) Complete genome, no data WP_073928710.1 (7e- WP_073928710.1 (2e- WP_073928710.1 (1e- NZ_LWLA00000000.1, Potential abyssomicin BGC, Streptomyces sp. CB03911 08/30.43%) 45/57.81%) 06/29.17%) 49 contigs, Illumina MiSeq partial WP_123627591.1 (6e- WP_123627591.1 (9e- WP_123627591.1 (8e- NZ_RJKF00000000.1, Streptomyces sp. E5N91 SAI-083 Potential BGC, total 22/34.55%) 15/36.90%) 13/32.35%) 2 contigs, PacBio WP_091120898.1 (2e- NZ_FMHY00000000.1, Micromonospora eburnea DSM 44814 No hit No hit Potential BGC, partial 14/34.23%) 2 contigs, no data WP_055751820.1 (1e- WP_055751820.1 (1e- WP_055751820.1 (1e- NZ_LJFZ00000000.1, Frankia sp. AvcI1 Abyssomicin BGC, partial 08/29.70%) 64/73.44%) 09/30.53%) 77 contigs, Illumina HiSeq WP_131760470.1 (2e- WP_131760470.1 (6e- CAACUY000000000, Actinomadura fibrosa LMG 29177 No hit Not enough data 12/32.71%) 07/30.70%) 569 contigs, no data WP_011605212.1 (2e- WP_011605212.1 (1e- WP_011605212.1 (1e- NC_008278, Frankia alni ACN14A Abyssomicin BGC, partial 08/29.70%) 65/74.22%) 10/31.58%) Complete genome, no data WP_018506019.1 (1e- WP_018506019.1 (1e- WP_018506019.1 (4e- NZ_ARDT00000000.1, Frankia discariae BCU110501 Abyssomicin BGC, partial 54/74.05%) 08/36.14%) 14/36.96%) 200 contigs, no data WP_020461028.1 (4e- WP_020461028.1 (2e- WP_020461028.1 (3e- NC_009921.1, Frankia sp. EAN1pec Abyssomicin BGC, total 56/75.57%) 08/36.14%) 14/35.64%) Complete genome, no data WP_066064649.1 (2e- WP_066064649.1 (1e- WP_066064649.1 (1e- NZ_LRTK01000000, Frankia sp. EI5c Abyssomicin BGC, partial 19/34.31%) 06/29.29% ) 17/42.05%) 159 contigs, Illumina HiSeq NC_015656.1, WP_043605928.1 (5e- WP_043605928.1 (6e- WP_043605928.1 (3e- Potential abyssomicin BGC, Frankia symbiont of Datisca glomerata Complete genome, 12/35.19%) 51/62.50%) 12/33.67%) partial 454/Illumina Frankia sp. Cc1.17 WP_071083475.1 (1e- WP_071084438.1 (2e- WP_071084438.1 (1e- NZ_MBLM00000000, 2 Abyssomicin BGCs, partial

22 35/51.33%) 17/42.05%) WP_071084438.1 (3e- 19/34.31%) 06/28.28%) WP_071083475.1 (8e- 195 contigs, Illumina HiSeq WP_131803042.1 (6e- 06/28.57%) 10/28.97%) Photobacterium ganghwense JCM WP_047885918.1 (1e- WP_047885918.1 (4e- NZ_PYMI00000000, No hit Not a BGC 12487 09/34.26%) 12/28.49%) 39 contigs, Illumina MiSeq WP_105971044.1 (1e- WP_105971044.1 (4e- WP_105971044.1 (7e- NZ_PJME00000000.1, Streptomyces geranii A301 Not enough data 18/36.09%) 10/34.19%) 16/36.80%) 104 contigs, Illumina HiSeq WP_121798615.1 (3e- WP_121798615.1 (3e- WP_121798615.1 (2e- NZ_PENC00000000, Streptomyces griseocarneus 132 Not enough data 26/40.00%) 07/29.41%) 10/27.21%) 227 contigs, Illumina HiSeq Streptomyces griseorubiginosus SAI- WP_123763217.1 (1e- WP_123763217.1 (1e- WP_123763217.1 (3e- NZ_RJKZ00000000, Potential abyssomicin BGC, 142 15/38.04%) 07/28.69%) 14/31.90%) 4 contigs, PacBio partial NZ_BBXF01000001, WP_062428853.1 (4e- WP_062428853.1 (5e- WP_062428853.1 (2e- Herbidospora daliensis NBRC 106372 Complete genome, Illumina Abyssomicin BGC, partial 63/76.56%) 10/37.35%) 15/38.64%) MiSeq Herbidospora mongoliensis NBRC WP_066363831.1 (6e- WP_066363831.1 (4e- WP_066363831.1 (9e- NZ_BBXD00000000, Abyssomicin BGC, total 105882 63/76.56%) 09/32.98%) 15/37.50%) 47 contigs, Illumina MiSeq Herbidospora sakaeratensis NBRC WP_062343027.1 (2e- WP_062343027.1 (6e- WP_062343027.1 (2e- NZ_BBXC00000000, Abyssomicin BGC, partial 102641 63/75.38%) 10/37.35%) 15/38.64%) 45 contigs, Illumina MiSeq NZ_AXWW00000000, WP_084467520.1 (9e- WP_084467520.1 (7e- Potential abyssomicin BGC, Actinokineospora inagensis DSM 44258 No hit 106 contigs,Illumina HiSeq 16/37.74%) 10/37.00%) partial 2000 WP_078957139.1 (8e- WP_078957139.1 (9e- WP_078957139.1 (8e- NZ_LK022848, Streptomyces iranensis DSM 41954 Potential BGC, partial 23/32.54%) 15/38.10%) 13/32.58%) Complete genome, no data WP_086666194.1 (3e- WP_086666194.1 (1e- NZ_MUYM00000000, Potential abyssomicin BGC, Lentzea kentuckyensis NRRL B-24416 No hit 13/38.30%) 06/28.03%) 317 contigs, Illumina MiSeq partial WP_116178805.1 (2e- WP_116178805.1 (3e- WP_116178805.1 (8e- NZ_QUNO00000000, Potential abyssomicin BGC, Kutzneria buriramensis DSM 45791 10/33.94% ) 50/61.72%) 10/28.23%) 65 contigs,Illumina HiSeq partial WP_114017401.1 (2e- WP_114017401.1 (2e- NZ_QOIM00000000, Streptomyces sp. LHW50302 No hit Not enough data 05/27.27%) 14/33.83%) 70 contigs,Illumina HiSeq Microbispora triticiradicis NEAU- WP_117409467.1 (2e- WP_117409467.1 (1e- WP_117409467.1 (2e- NZ_QFZU00000000, Potential abyssomicin BGC, HRDPA2-9 07/33.73%) 76/80.60%) 11/29.01%) 285 contigs,Illumina HiSeq partial Micromonospora wenchangensis WP_088646687.1 (2e- WP_088646687.1 (7e- WP_088646687.1 (8e- NZ_MZMV00000000.1, Abyssomicin BGC, partial CCTCC AA 2012002 72/85.11%) 11/38.55%) 13/35.63%) 150 contigs,Illumina HiSeq WP_107157684.1 (2e- WP_107157684.1 (6e- WP_107157684.1 (2e- NZ_PYPS00000000, Potential abyssomicin BGC, Micromonospora sp. RP3T 23/40.19%) 16/32.85%) 25/38.40%) 174 contigs,Illumina HiSeq partial Streptomyces monomycini NRRL B- WP_050502808.1 (2e- WP_050502808.1 (5e- WP_050502808.1 (7e- NZ_JNYL00000000, Not enough data 24309 15/36.08%) 07/33.72% ) 24/37.59%) 643 contigs,Illumina WP_071375955.1 (1e- WP_071375955.1 (2e- WP_071375955.1 (8e- NZ_MLYN00000000, Streptomyces sp. MUSC 14 Potential BGC, partial 24/41.44%) 13/35.63%) 11/30.39%) 174 contigs, Illumina MiSeq WP_069626275.1 (9e- WP_069626275.1 (5e- WP_069626275.1 (4e- NZ_MDCR00000000, Potential abyssomicin BGC, Streptomyces niveus NRRL 2466 11/29.70%) 15/28.87%) 76/53.02%) 608 contigs, Illumina MiSeq partial WP_124445689.1 (5e- WP_124445689.1 (8e- WP_124445689.1 (2e- NZ_BHXA00000000, 17/35.83%) 11/34.19%) 13/36.73%) Potential abyssomicin BGC, Streptomyces sp. NL15-2K 292 contigs, Illumina WP_124445685.1 (7e- WP_124445685.1 (6e- WP_124445685.1 (2e- partial HiSeq2500 17/39.56%) 08/30.34%) 11/33.70%)

23 WP_033287247.1 (1e- WP_033287247.1 (4e- 20/39.50%) WP_033287156.1 (6e- 12/34.78%) NZ_JNXE00000000, Potential abyssomicin BGC, Streptomyces sp. NRRL F-525 WP_033287156.1 (6e- 09/29.56%) WP_033287156.1 (2e- 242 contigs, Illumina partial 09/33.33%) 07/29.21% ) WP_030904231.1 (3e- NZ_JOFZ00000000, Potential abyssomicin BGC, Streptomyces sp. NRRL F-5126 No hit No hit 12/35.11%) 168 contigs, Illumina partial WP_053700241.1 (2e- WP_053700241.1 (2e- NZ_LGCW00000000, Streptomyces sp. NRRL F-5755 No hit Not enough data 12/36.70%) 22/36.59%) 327 contigs, Illumina HiSeq WP_030750288.1 (3e- 35/49.22%) WP_030750286.1 (4e- NZ_JOCB00000000, Streptomyces sp. NRRL S-31 No hit Not enough data WP_030750286.1 (1e- 08/29.03%) 322 contigs, Illumina 15/32.71%) WP_031075100.1 (3e- WP_031075100.1 (6e- NZ_JOCF01000000, Potential abyssomicin BGC, Streptomyces sp. NRRL WC-3742 No hit 09/33.33%) 45/57.48% ) 233 contigs, Illumina partial KDN76177.1 (2e- KDN76177.1 (3e- JJOH00000000, Potential tetronomycin BGC, Streptomyces olindensis DAUFPE 5622 No hit 11/31.15%) 06/28.30%) 233 contigs, Illumina total AFI57012.1 (4e- AFI57012.1 (6e- JF970188, Amycolatopsis orientalis Q427-8 No hit Quartromicin BGC, total 09/36.75%) 06/30.82%) Quartromicin BGC, no data WP_017346023.1 (1e- WP_017346023.1 (9e- NZ_ALXE00000000, Pantoea sp. A4 No hit Potential BGC, partial 08/31.18%) 11/28.87%) 71 contigs, Illumina HiSeq Streptomyces paucisporeus CGMCC WP_073498104.1 (8e- WP_073498104.1 (6e- WP_073498104.1 (4e- NZ_FRBI00000000, Potential abyssomicin BGC, 4.2025 13/33.33%) 11/29.17%) 08/28.71%) 79 contigs, no data partial WP_121438130.1 (2e- WP_121438130.1 (1e- WP_121438130.1 (3e- NZ_RBWU00000000, Potential chlorothricin BGC, Actinomadura pelletieri DSM 43383 16/40.00% ) 07/25.83%) 09/29.66%) 15 contigs, Illumina HiSeq partial Candidatus Streptomyces philanthi WP_114021297.1 (4e- WP_114021297.1 (6e- NZ_QOIN00000000, No hit Potential BGC, partial LHW51701 06/29.09%) 14/33.83%) 80 contigs, Illumina MiSeq Streptomyces rimosus subsp. rimosus WP_033030402.1 (2e- WP_033030402.1 (8e- NZ_JNWX00000000, No hit Potential BGC, partial NRRL B-16073 10/38.14%) 23/34.76%) 140 contigs, Illumina WP_027758722.1 (1e- WP_027758722.1 (6e- WP_027758722.1 (3e- NZ_ARPE00000000, Streptomyces sp. Amel2xE9 Abyssomicin BGC, partial 11/39.76%) 91/98.44%) 15/32.08%) 73 contigs, no data WP_106434019.1 (1e- WP_106434019.1 (1e- WP_106434019.1 (4e- NZ_ACUR01000000, Streptomyces sp. e14 Abyssomicin BGC, partial 11/39.76% ) 125/100.00%) 15/31.34%) 13 scaffolds, ABI WP_108952931.1 (5e- WP_108952931.1 (2e- WP_108952931.1 (2e- NZ_BEVZ00000000, Streptomyces fragilis NBRC 12862 Abyssomicin BGC, partial 65/78.46%) 10/36.73%) 16/38.64%) 19 contigs, Illumina MiSeq AKJ08822.1 (1e- AKJ08822.1 (4e- AKJ08822.1 (3e- CP011497, Potential abyssomicin BGC, Streptomyces incarnatus NRRL 8089 12/33.91%) 52/60.58%) 13/33.08%) Complete genome, 454 partial WP_053650217.1 (3e- WP_053650217.1 (1e- WP_053650217.1 (7e- NZ_LGEE00000000, Streptomyces sp. NRRL F-6491 Abyssomicin BGC, partial 10/36.14%) 115/91.81%) 17/32.84%) 287 contigs, Illumina HiSeq WP_037772597.1 (3e- WP_037772597.1 (1e- WP_037772597.1 (3e- NZ_CP016795, Streptomyces olivaceus KLBMP 5084 Potential BGC, total 21/34.55% ) 14/36.90%) 12/32.35%) Complete genome, PacBio WP_062712130.1 (8e- WP_062712130.1 (9e- WP_062712130.1 (7e- NZ_LLZG00000000, Potential abyssomicin BGC, Streptomyces regalis NRRL 3151 66/78.46%) 09/34.94%) 16/38.64%) 424 contigs, Illumina HiSeq partial KMS84434.1 (1e- KMS84434.1 (1e- KMS84434.1 (2e- LFVR00000000, Potential abyssomicin BGC, Streptomyces regensis NRRL B-11479 63/76.92%) 08/37.00% ) 17/40.91% ) 960 contigs, Illumina HiSeq partial Saccharothrix syringae NRRL B-16468 WP_033431227.1 (4e- WP_033434419.1 (4e- WP_033431227.1 (3e- NZ_JNYO00000000, Abyssomicin BGC, partial 23/34.13%) 49/59.38%) 13/33.71%) 190 contigs, Illumina WP_033434419.1 (5e- WP_033431227.1 (8e- WP_033434419.1 (2e- Potential BGC, total

24 11/32.17%) 16/39.29%) 11/33.33%) WP_129847681.1 (2e- WP_129847681.1 (4e- WP_129847681.1 (9e- NZ_PKMX00000000, Streptomyces sp. SCA2-2 Abyssomicin BGC, partial 15/33.93%) 15/31.34%) 158/99.09%) 48 contigs, Illumina HiSeq WP_093830612.1 (2e- WP_093830612.1 (8e- WP_093830612.1 (4e- NZ_FMCI00000000, Streptomyces sp. SolWspMP-5a-2 Not enough data 13/36.17%) 06/31.00%) 06/28.09%) 400 contigs, no data NZ_CP031264.1, WP_111492780.1 (9e- WP_111492780.1 (3e- WP_111492780.1 (4e- Potential abyssomicin BGC, Streptacidiphilus sp. DSM 106435 Complete genome, PacBio 07/32.46%) 47/60.16% ) 06/29.17%) partial RSII and Illumina MiSeq WP_120684678.1 (1e- WP_120684678.1 (5e- WP_120684678.1 (9e- NZ_RBAL00000000.1, Streptomyces hoynatensis KCTC 29097 Not enough data 08/31.87%) 11/29.06%) 12/30.84% ) 53 contigs, Illumina MiSeq RLK30369.1 (2e- RLK30369.1 (7e- RCCZ00000000.1, Streptomyces sp. 57 No hit Abyssomicin BGC, total 52/71.76%) 11/38.64%) 8 contigs, PacBio Streptomyces subroseum CGMCC WP_089206782.1 (2e- WP_089206782.1 (9e- WP_089206782.1 (8e- NZ_FZOD00000000.1, Potential abyssomicin BGC, 4.2132 08/33.73%) 75/82.81%) 12/28.23%) 180 scaffolds, no data partial Streptomyces varsoviensis NRRL B- WP_030882074.1 (6e- WP_030882074.1 (4e- WP_030882074.1 (8e- NZ_JOFN00000000.1, Potential BGC, total 3589 21/35.45%) 15/36.90%) 14/33.33%) 155 contigs, Illumina Potential abyssomicin BGC, - - - NZ_SLWS00000000.1, partial Actinocrispum wychmicini DSM 45934 WP_132116074.1 (9e- WP_132116074.1 (1e- 43 Scaffolds, Illumina Potential chlorothricin BGC, No hit 17/42.39%) 07/37.31%) partial

25 Table S10. The abyssomicin biosynthetic gene cluster from M. maris AB-16-032 (modified from Gottardi et al., 2011).

Size Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog abyR 248 transcriptional regulator, SARP family SARP family transcriptional regulator, Verrucosispora maris (WP_013733064.1); 99/100 - - abyX 396 cytochrome P450 cytochrome P450, Micromonospora wenchangensis (WP_088646685.1); 82/90 AbsX - abyH 889 LuxR family transcriptional regulator helix-turn-helix transcriptional regulator, Verrucosispora sp. FIM060022 (WP_126713160.1); 99/99 - AbmH abyI 252 transcriptional regulator, SARP family putative pathway specific activator, Streptomyces longisporoflavus (ACR50789.1); 49/63 - AbmI abyU 141 Diels–Alderase YD repeat-containing protein, Verrucosispora sp. MS100047 (AIS85752.1); 100/100 AbsU AbmU abyK 619 YD repeat RHS repeat protein, Verrucosispora sp. FIM060022 WP_126713159.1] 99/99 - - 3-oxoacyl-ACP synthase III family protein, Verrucosispora sp. FIM060022 (WP_126713158.1); abyA1 341 β-ketoacyl-acyl-carrier protein synthase I AbsA1 AbmA1 99/99 abyA2 622 phosphatase and glyceryl transferase FkbH like protein, Verrucosispora sp. MS100047 (AIS85751.1); 99/99 AbsA2 AbmA2 abyA3 78 discrete ACP acyl carrier protein, Verrucosispora sp. FIM060022 (RUL90284.1); 99/100 AbsA3 AbmA3 dehydrogenase catalytic domain-containing dehydrogenase catalytic domain-containing protein, Verrucosispora sp. MS100047 (AIS85747.1); abyA4 251 AbsA4 AbmA4 protein 99/99 hydrolase superfamily dihydrolipoamide abyA5 355 alpha/beta hydrolase, Verrucosispora sp. FIM060022 (WP_126713156.1); 99/99 AbsA5 AbmA5 acyltransferase-like protein abyB1 5781 PKS I type I polyketide synthase, Streptomyces sp. KhCrAH-43 (WP_018522876.1); 54/63 AbsB1 AbmB1 abyB2 3645 PKS I type I polyketide synthase, Streptomyces sp. 2131.1 (WP_093709984.1); 54/63 AbsB2 AbmB2 acyltransferase domain-containing protein, Verrucosispora sp. FIM060022 (WP_126713147.1); abyB3 992 PKS I AbsB3 AbmB3 99/99 abyC 230 regulatory protein, TetR TetR family transcriptional regulator, Verrucosispora sp. FIM060022 (WP_126713146.1); 100/100 - AbmC abyD 475 drug resistance transporter EmrB/QacA DHA2 family efflux MFS transporter, Micromonospora wenchangensis (WP_088644887.1); 86/92 AbsD AbmD LLM class flavin-dependent oxidoreductase, Verrucosispora sp. FIM060022 (RUL90371.1); abyE 335 luciferase; alkanal monooxygenase α-chain AbsE AbmE1 100/100 ABC transporter periplasmic peptide-binding abyF1 538 ABC transporter substrate-binding protein, Verrucosispora sp. FIM060022 (RUL90370.1); 100/100 AbsF1 AbmF1 protein abyF2 311 ABC transporter inner membrane component ABC transporter permease, Micromonospora wenchangensis (WP_088644890.1); 82/89 AbsF2 AbmF2 abyF3 283 ABC transporter inner membrane component ABC transporter permease, Verrucosispora sp. FIM060022 (WP_126713145.1); 99/99 AvsF3 AbmF3 dipeptide ABC transporter ATP-binding protein, Verrucosispora sp. FIM060022 abyF4 539 ABC transporter ATP-binding protein AbsF4 AbmF4 (WP_126713144.1); 99/99 abyV 395 cytochrome P450 cytochrome P450, Verrucosispora sp. FIM060022 (WP_126713143.1); 99/99 AbsV AbmV abyW 83 alcohol dehydrogenase zinc-binding domain Ferredoxin, Verrucosispora sp. FIM060022 (WP_126713142.1); 98/100 - - abyZ 192 NAD(P)H-dependent FMN reductase FMN reductase (NADPH), Verrucosispora sp. FIM060022 (WP_126713141.1); 99/100 AbsH1 AbmZ abyT 298 thioesterase Thioesterase, Verrucosispora sp. FIM060022 (RUL90363.1); 100/100 AbsN AbmT

26 Table S11. The abyssomicin biosynthetic gene cluster from S. koyangensis SCSIO 5802 (modified from Song et al., 2017).

Size Aby Abs ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog abmN 445 rRNA (Uracil-5-)-methyltransferase RlmD, Acinetobacter baumannii AB307-0294 (B7H018.1); 30/48 - - abmI 268 Transcriptional activator, SARP family DnrI, Streptomyces peucetius (P25047.1); 35/50 AbyI - abmE2 356 Luciferase-like monooxygenase, α-subunit LuxA, Photorhabdus luminescens (P23146.1); 24/42 - - abmU 218 Diels–Alderase YD repeat-containing protein, Streptomyces regensis (KMS84434.1); 41/52 AbyU AbsU abmK 256 4′-Phosphopantetheinyl transferase superfamily (PPTase) Npt, Nocardia iowensis (A1YCA5.1); 42/54 - - abmL 281 Metallophosphoesterase GsiA, Salmonella enterica (Q57RB2.2); 46/60 - - abmF4 560 ABC transporter system ATP-binding protein OppD, Lactococcus lactis (AIS04392.1); 42/73 AbyF4 AbsF4 ABC transporter system substrate-binding protein abmF3 298 OppC, Lactococcus lactis (ABA47380.1); 27/63 AbyF3 AbsF3 dependent permease abmM 413 Amidohydrolase Mb2939c, Mycobacterium bovis AF2122/97 (P68916.1); 28/37 - - abmF2 313 ABC transporter system permease OppB, Lactococcus lactis (ABA47381.1); 27/58 AbyF2 AbsF2 abmF1 546 ABC transport system substrate-binding protein OppA, Lactococcus lactis (AAO63469.1); 20/52 AbyF1 AbsF1 abmJ 331 Aldo/keto reductase OsI_15387, Oryza sativaIndica (A2XRZ0.1); 50/68 - AbsJ abmG 77 Ferredoxin Fd-1, Streptomyces griseolus (P18324.3); 58/75 - AbsG1 abmV 405 Cytochrome P450 Vitamin D3 dihydroxylase, Streptomyces griseolus (P18326.2); 55/70 AbyV AbsV abmC 257 TetR regulatory protein Mce3R, Mycobacterium tuberculosis H37Rv (P95251.2); 33/48 AbyC - abmE1 353 Luciferase-like monooxygenase, β-subunit LuxB, Photorhabdus luminescens (P19840.1); 20/41 AbyE AbsE abmD 487 Major facilitator superfamily of transporter EmrB, Mycobacterium tuberculosis CDC1551 (P9WG88.1); 34/56 AbyD AbsD abmA1 343 Ketoacyl-S-ACP synthase ChlM, Streptomyces antibioticus (AAZ77702.1); 61/74 AbyA1 AbsA1 abmA2 628 Glyceryl-S-ACP synthase ChlD, Streptomyces antibioticus (AAZ77703.1); 61/70 AbyA2 AbsA2 abmA3 75 Acyl carrier protein ChlD2, Streptomyces antibioticus (AAZ77704.1); 56/73 AbyA3 AbsA3 2-Oxoacid dehydrogenase multienzymes acyltransferase abmA4 280 ChlD3, Streptomyces antibioticus (AAZ77705.1); 65/76 AbyA4 AbsA4 E2 component abmA5 373 α/β hydrolase fold protein ChlD4, Streptomyces antibioticus (AAZ77706.1); 51/64 AbmA5 AbsA5 abmT 274 Type II thioesterase PikA5, Streptomyces venezuelae (Q9ZGI1.1); 32/45 AbyT AbsN abmZ 178 NADPH-dependent flavin reductase HsaB, Rhodococcus jostii RHA1 (Q0S808.1); 39/57 AbyZ AbsH1 abmB1 6540 PKS I PikA1, Streptomyces venezuelae (Q9ZGI5.1); 54/65 AbyB1 AbsB1 abmB2 4054 PKS I PikA2, Streptomyces venezuelae (Q9ZGI4.1); 49/59 AbyB2 AbsB2

27 abmB3 1040 PKS I PikA1, Streptomyces venezuelae (Q9ZGI5.1); 54/64 AbyB3 AbsB3 abmH 942 LuxR family transcriptional regulator NreC, Staphylococcus carnosus subsp. carnosus TM300 (Q7WZY4.1); 48/67 AbyH -

28 Table S12. The abyssomicin biosynthetic gene cluster from Streptomyces sp. LC-6-2 (adapted from Wang et al., 2017).

Size Aby Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog short-chain dehydrogenase/reductase family oxidoreductase, Streptomyces sp. E14 (EFF94110.1); absM 187 short chain dehydrogenase - - 97/98 absP 301 alpha/beta hydrolase alpha/beta fold hydrolase, Streptomyces sp. E14 (WP_009191652.1); 99/99 - - absK 209 histidine phosphatase family protein histidine phosphatase family protein, Streptomyces sp. E14 (WP_009191653.1); 97/98 - - absC1 237 TetR family transcription regulator TetR family transcriptional regulator, Streptomyces sp. E14 (EFF94113.1); 99/100 - - absH3 387 Oxidoreductase oxidoreductase, Streptomyces sp. E14 (WP_009191655.1); 98/98 - - absH2 117 Oxidoreductase oxidoreductase, Streptomyces scabrisporus (WP_026218602.1); 85/90 - - absH1 185 NADPH-dependent flavin reductase flavin reductase domain-containing protein, Streptomyces sp. E14 (EFF94116.1); 99/100 AbyZ AbmZ absA1 351 oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. E14 (WP_063821841.1); 100/100 AbyA1 AbmA1 absA3 77 acyl carrier protein acyl carrier protein, Streptomyces sp. E14 (WP_043261562.1); 100/100 AbyA3 AbmA3 absA4 251 2-oxoacid dehydrogenases acyltransferase acyltransferase, Microbispora triticiradicis (WP_111700702.1); 82/88 AbyA4 AbmA4 hydrolase superfamily dihydrolipoamide absA5 381 alpha/beta hydrolase, Streptomyces sp. Amel2xE9 (WP_019984789.1); 98/98 AbmA5 AbmA5 acyltransferase-like protein absN 275 thioesterase thioesterase, Streptomyces sp. E14 (WP_009191660.1); 99/99 AbyT AbmT absB1 6424 PKS I type I polyketide synthase, Streptomyces sp. Amel2xE9 (WP_078625043.1); 97/97 AbyB1 AbmB1 absB2 3644 PKS I type I polyketide synthase, Streptomyces sp. Amel2xE9 (WP_019985563.1); 95/95 AbyB2 AbmB2 absB3 1049 PKS I type I polyketide synthase, Streptomyces sp. Amel2xE9 (WP_019985562.1); 98/98 AbyB3 AbmB3 absA2 649 FkbH-like protein HAD-IIIC family phosphatase, Streptomyces sp. Amel2xE9 (WP_019985561.1); 99/99 AbyA2 AbmA2 LLM class flavin-dependent oxidoreductase, Streptomyces sp. Amel2xE9 (WP_106962181.1); absE 328 FMN-dependent alkanal monooxygenase AbyE AbmE 99/99 absF1 554 ABC transporter ABC transporter substrate-binding protein, Streptomyces sp. Amel2xE9 (WP_027758725.1); 99/99 AbyF1 AbmF1 absF2 333 ABC transporter ABC transporter permease, Streptomyces sp. Amel2xE9 (WP_019985558.1); 99/99 AbyF2 AbmF2 absF3 269 ABC transporter ABC transporter permease, Streptomyces sp. Amel2xE9 (WP_106962190.1); 99/99 AbyF3 AbmF3 absF4 555 ABC transporter ABC transporter ATP-binding protein, Streptomyces sp. Amel2xE9 (WP_019985556.1); 98/98 AbyF4 AbmF4 absV 397 cytochrome P450 cytochrome P450, Streptomyces sp. Amel2xE9 (WP_027758724.1); 99/100 AbyV AbmV absG1 68 ferredoxin ferredoxin-1, Streptomyces sp. NRRL F-6491 (KOX15570.1); 84/94 - AbmG absI 387 acyltransferase acyltransferase, Streptomyces sp. E14 (WP_009191675.1); 100/100 - - absX 403 cytochrome P450 cytochrome P450, Streptomyces sp. E14 (WP_009191676.1); 100/100 AbyX - absG2 64 Ferredoxin ferredoxin-1, Streptomyces sp. NRRL F-6491 (KOX15554.1); 89/95 - -

29 absJ 344 aldo/keto reductase aldo/keto reductase, Streptomyces sp. E14 (WP_050790870.1); 100/100 - AbmJ absU 171 Diels-Alderase hypothetical protein, Streptomyces sp. E14 (WP_106434019.1); 100/100 AbyU AbmU absC2 196 TetR familt transcription regulator TetR/AcrR family transcriptional regulator, Streptomyces sp. E14 (WP_009191680.1); 99/99 - - absD 476 MFS transporter MFS transporter, Streptomyces sp. E14 (WP_043261567.1); 100/100 AbyD AbmD

30 Table S13. The abyssomicin biosynthetic gene cluster from Verrucosispora sp. MS100047 (KF826681.1).

Size Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog VASRM7_503 355 hypothetical protein AbyA5, Verrucosispora maris AB-18-032 (AEK75501.1); 99/99 AbsA5 AbmA5 dehydrogenase catalytic domain-containing VASRM7_504 251 acyltransferase, Verrucosispora maris (WP_013733055.1); 99/99 AbsA4 AbmA4 protein VASRM7_505 78 hypothetical protein acyl-carrier protein, Verrucosispora maris AB-18-032 (AEK75499.1); 100/100 AbsA3 AbmA3 VASRM7_508 622 FkbH like protein FkbH like protein, Verrucosispora maris AB-18-032 (AEB44397.1); 99/99 AbsA2 AbmA2 VASRM7_506 341 3-oxoacyl-[acyl-carrier-protein Chain A, 3-oxoacyl-acp Synthase III, Verrucosispora maris AB-18-032 (5BY7_A); 99/99 AbsA1 AbmA1 VASRM7_507 579 YD repeat-containing protein RHS repeat protein, Verrucosispora sp. FIM060022 (WP_126713159.1); 99/100 - - VASRM7_509 141 YD repeat-containing protein YD repeat-containing protein, Verrucosispora maris AB-18-032 (AEB44400.1); 100/100 AbsU AbmU SARP family pathway specific SARP family pathway specific transcriptional activator, Verrucosispora maris AB-18-032 VASRM7_510 241 - AbmI transcriptional activator (AEB44401.1); 100/100 VASRM7_511 288 hypothetical protein - - -

31 Table S14. Predicted functions of ORFs in abyssomicin BGC from Actinokineospora auranticolor YU 961-1 (PTIX01000001.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog 3-oxoacyl-[acyl-carrier-protein] 3-oxoacyl-ACP synthase III family protein, Microbispora triticiradicis CLV40_RS02920 314 AbyA1 AbsA1 AbmA1 synthase-3 (WP_111700704.1); 76/84 CLV40_RS02925 74 phosphopantetheine binding protein acyl carrier protein, Actinocrispum wychmicini (WP_132114012.1); 58/75 AbyA3 AbsA3 AbmA3 2-oxoacid CLV40_RS02930 247 acyltransferase, Microbispora triticiradicis (WP_111700702.1); 70/77 AbyA4 AbsA4 AbmA4 dehydrogenase/acyltransferase alpha/beta hydrolase family protein CLV40_RS02935 357 alpha/beta hydrolase, Microbispora triticiradicis (WP_111700701.1); 66/78 AbyA5 AbsA5 AbmA5 DUF1100 surfactin synthase thioesterase CLV40_RS02940 237 thioesterase, Microbispora triticiradicis (WP_111700742.1); 55/64 AbyT AbsN AbmT subunit CLV40_RS02945 5456 PKS I putative type I polyketide synthase, Frankia alni ACN14a (CAJ62714.1); 53/62 AbyB1 AbsB1 AbmB1 CLV40_RS02950 3217 PKS I type I polyketide synthase, Frankia sp. AvcI1 (WP_055752030.1); 58/67 AbyB2 AbsB2 AbmB2 CLV40_RS02955 989 PKS I acyltransferase domain-containing protein, Frankia alni (WP_011605200.1); 58/67 AbyB3 AbsB3 AbmB3 HAD superfamily phosphatase CLV40_RS02960 629 (TIGR01681 family)/FkbH-like HAD-IIIC family phosphatase, Frankia alni (WP_011605199.1); 63/72 AbyA2 AbsA2 AbmA2 protein transposase IS4 family protein, Saccharomonospora azurea SZMC 14600 CLV40_RS02965 161 DDE superfamily endonuclease - - - (EHK83939.1); 51/67 luciferase family oxidoreductase LLM class flavin-dependent oxidoreductase, Streptomyces sp. Amel2xE9 CLV40_RS02970 332 AbyE AbsE1 AbmE1 group 1 (WP_106962181.1);68/76 peptide/nickel transport system ABC transporter substrate-binding protein, Microbispora triticiradicis CLV40_RS02975 542 AbyF1 AbsF1 AbmF1 substrate-binding protein (WP_117408852.1); 62/73 peptide/nickel transport system ABC transporter permease, Streptosporangium subroseum (WP_089206641.1); CLV40_RS02980 278 AbyF2 AbsF2 AbmF2 permease protein 68/80 peptide/nickel transport system CLV40_RS02985 270 ABC transporter permease, Actinocorallia herbida (WP_123665082.1); 61/72 AbyF3 AbsF3 AbmF3 permease protein peptide/nickel transport system ATP- ABC transporter ATP-binding protein, Streptosporangium subroseum CLV40_RS02990 535 AbyF4 AbsF4 AbmF4 binding protein (WP_089206779.1); 66/74 CLV40_RS02995 396 pentalenic acid synthase cytochrome P450, Microbispora triticiradicis (WP_117409456.1); 74/85 AbyV AbsV AbmV CLV40_RS03000 63 ferredoxin ferredoxin, Streptosporangium subroseum (WP_089206642.1); 61/76 - AbsG1 AbmG aryl-alcohol dehydrogenase-like CLV40_RS03005 333 aldo/keto reductase, Microbispora triticiradicis (WP_117409459.1); 69/78 - AbsJ AbmJ predicted oxidoreductase CLV40_RS03010 131 Diels-Alderase hypothetical protein, Streptomyces sp. E14 (WP_106434019.1); 68/77 AbyU AbsU AbmU LuxR family transcriptional regulator, Microbispora triticiradicis (WP_133306130.1); CLV40_RS03015 915 regulatory LuxR family protein AbyH - AbmH 55/67 TetR/AcrR family transcriptional regulator, Microbispora sp. GKU 823 CLV40_RS03020 213 AcrR family transcriptional regulator - AbsC2 - (WP_079317081.10; 73/84 EmrB/QacA drug resistance CLV40_RS03025 480 MFS transporter, Saccharothrix syringae (WP_033434362.1);62/75 AbyD AbsD AbmD transporter

32 SARP family transcriptional regulator, Micromonospora wenchangensis CLV40_RS03030 277 SARP family transcriptional regulator AbyI - AbmI (WP_088646684.1); 74/82

33 Table S15. Predicted functions of ORFs in abyssomicin BGC from Actinokineospora auranticolor YU 961-1 (PTIX01000011.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog CLV40_RS20825 402 cytochrome P450 cytochrome P450, Frankia sp. Cc1.17 (WP_071083429.1); 65/77 AbyV AbsV AbmV CLV40_RS20830 171 Diels-Alderase hypothetical protein, Streptomyces sp. NRRL S-31 (WP_030750286.1); 53/64 AbyU AbsU AbmU CLV40_RS20835 155 Diels-Alderase hypothetical protein, Streptomyces sp. NRRL S-31 (WP_030750288.1); 60/76 AbyU AbsU AbmU 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. NRRL S-31 CLV40_RS20840 343 AbyA1 AbsA1 AbmA1 family protein (WP_030750290.1); 70/83 CLV40_RS20845 631 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Kutzneria buriramensis (WP_116181645.1); 61/73 AbyA2 AbsA2 AbmA2 CLV40_RS20850 75 acyl carrier protein acyl carrier protein, Streptomyces sp. NRRL F-5123 (WP_031525362.10; 54/79 AbyA3 AbsA3 AbmA3 CLV40_RS20855 230 acyltransferase acyltransferase, Actinomadura pelletieri (WP_121438112.1); 63/73 AbyA4 AbsA4 AbmA4 CLV40_RS20860 358 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces sp. 2131.1 (WP_093709996.1); 59/70 AbyA5 AbsA5 AbmA5 CLV40_RS20865 6037 PKS I type I polyketide synthase, Streptomyces fragilis (WP_108952947.1); 54/62 AbyB1 AbsB1 AbmB1 CLV40_RS20870 3369 PKS I type I polyketide synthase, Actinomadura macra (WP_067456430.1); 49/58 AbyB2 AbsB2 AbmB2 CLV40_RS20875 1036 PKS I type I polyketide synthase, Streptomyces regalis (WP_062710596.1); 53/64 AbyB3 AbsB3 AbmB3 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. Cc1.17 (WP_071083425.1); CLV40_RS20880 347 - - AbmE2 oxidoreductase 68/80 CLV40_RS20885 532 MFS transporter MFS transporter, Streptomyces regalis (KUL37079.10); 48/63 AbyD AbsD AbmD CLV40_RS20890 407 amidohydrolase family protein amidohydrolase family protein, Streptomyces sp. SCA2-2 (WP_129847676.1); 53/64 - - AbmM LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. Cc1.17 CLV40_RS20895 350 AbyE AbsE1 AbmE1 oxidoreductase (WP_071083424.1);60/71 TetR/AcrR family TetR/AcrR family transcriptional regulator, Streptomyces sp. CB02414 CLV40_RS20900 225 AbyC - AbmC transcriptional regulator (WP_073730525.1); 56/70 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Frankia sp. Cc1.17 CLV40_RS20905 483 AbyD AbsD AbmD transporter permease subunit (WP_071083423.1); 67/78 AfsR/SARP family AfsR/SARP family transcriptional regulator, Streptomyces sp. SA15 (WP_095750847.10; CLV40_RS20910 280 AbyI - AbmI transcriptional regulator 52/69 helix-turn-helix transcriptional CLV40_RS20915 885 hypothetical protein AMK11_25530, Streptomyces sp. CB02414 (OKI81332.1); 33/42 AbyH - AbmH regulator ABC transporter ATP-binding dipeptide ABC transporter ATP-binding protein, Actinocrispum wychmicini CLV40_RS20920 526 AbyF4 AbsF4 AbmF4 protein (WP_132114000.1); 61/71 CLV40_RS20925 282 ABC transporter permease ABC transporter permease, Actinomadura macra (WP_067456459.1); 68/79 AbyF3 AbsF3 AbmF3 CLV40_RS20930 288 ABC transporter permease ABC transporter permease subunit, Actinocrispum wychmicini (WP_132114004.1); 64/81 AbyF2 AbsF2 AbmF2 ABC transporter substrate- CLV40_RS20935 531 AbmF1, Streptomyces koyangensis (AVI57419.1); 54/67 AbyF1 AbsF1 AbmF1 binding protein

34 Table S16. Predicted functions of ORFs surrounding AbyU homolog from Actinomadura sp. H3C3 (NZ_SMKU01000406.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog E1298_RS41175 - PKS I type I polyketide synthase, Streptomyces iranensis (WP_044580929.1); 53/61 - - - TetR family transcriptional regulator, Streptomyces sp. NRRL F-525 E1298_RS41180 209 TetR family transcriptional regulator - - - (WP_078652913.1); 45/67 MMPL family transporter, Streptomyces sp. NRRL F-525 (WP_051801844.1); E1298_RS41185 722 MMPL family transporter - - - 60/70 E1298_RS41190 181 Diels-Alderase hypothetical protein, Actinomadura sp. 6K520 (WP_131984851.1); 31/51 AbyU AbsU AbmU

35 Table S17. Predicted functions of ORFs in quartromicin BGC from Amycolatopsis albispora WP1 (NZ_CP015163.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog A4R43_RS38100 399 cytochrome P450 cytochrome p450, Amycolatopsis orientalis (AFI57027.1); 95/97 - - - 2-oxoacid dehydrogenase, acyltransferase, Amycolatopsis orientalis A4R43_RS38105 267 acyltransferase - - - (AFI57026.1); 86/90 A4R43_RS38110 74 acyl carrier protein ACP, Amycolatopsis orientalis (AFI57025.1); 94/97 - - - glyceryltransferase/phosphatase, Amycolatopsis orientalis (AFI57024.1); A4R43_RS38115 609 HAD-IIIC family phosphatase - - - 91/94 3-oxoacyl-ACP synthase III (KS), Amycolatopsis orientalis (AFI57023.1); A4R43_RS38120 343 3-oxoacyl-ACP synthase III family protein - - - 95/98 A4R43_RS38125 221 response regulator transcription factor QmnRg3, Amycolatopsis orientalis (AFI57015.1); 99/99 - - - A4R43_RS38130 446 HAMP domain-containing protein QmnRg2, Amycolatopsis orientalis (AFI57016.1); 90/94 - - - A4R43_RS38135 150 hypothetical protein QmnL, Amycolatopsis orientalis (AFI57019.1); 88/90 - - - HlyD family efflux transporter periplasmic A4R43_RS38140 352 QmnK, Amycolatopsis orientalis (AFI57020.1); 96/97 - - - adaptor subunit A4R43_RS38145 227 ABC transporter ATP-binding protein QmnRs2, Amycolatopsis orientalis (AFI57021.1); 96/99 - - - A4R43_RS38150 406 ABC transporter permease QmnRs1, Amycolatopsis orientalis (AFI57022.1); 97/98 - - - A4R43_RS38155 160 hypothetical protein QmnJ, Amycolatopsis orientalis (AFI57014.1); 88/93 - - - HlyD family efflux transporter periplasmic A4R43_RS38160 348 QmnI, Amycolatopsis orientalis (AFI57013.1); 88/93 - - - adaptor subunit A4R43_RS38165 376 Diels-Alderase QmnH, Amycolatopsis orientalis (AFI57012.1); 94/97 AbyU AbsU AbmU PQQ-dependent dehydrogenase, Amycolatopsis orientalis (AFI57011.1); A4R43_RS38170 533 hypothetical protein - - - 93/95 hypothetical protein, Streptomyces sparsogenes (WP_065968263.1); A4R43_RS38175 72 hypothetical protein - - - 57/63 A4R43_RS38180 255 AfsR/SARP family transcriptional regulator regulator, Amycolatopsis orientalis (AFI57010.1); 98/98 - - - A4R43_RS38185 396 cysteine desulfurase-like protein QmnF, Amycolatopsis orientalis (AFI57009.1); 89/92 - - - A4R43_RS38190 383 hypothetical protein QmnE, Amycolatopsis orientalis (AFI57008.1); 90/93 - - - A4R43_RS38195 153 hypothetical protein - - - - A4R43_RS38200 1285 PKS I QmnA3, Amycolatopsis orientalis (AFI57007.1); 86/90 - - - A4R43_RS38205 1767 PKS I QmnA2, Amycolatopsis orientalis (AFI57006.1); 93/96 - - - A4R43_RS38210 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 92/94 - - - A4R43_RS38215 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 89/94 - - -

36 A4R43_RS38220 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 89/93 - - - A4R43_RS38225 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 92/94 - - - A4R43_RS38230 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 86/92 - - - A4R43_RS38235 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 91/95 - - - A4R43_RS38240 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 94/96 - - - A4R43_RS38245 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 91/93 - - - A4R43_RS38250 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 86/90 - - - A4R43_RS38255 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 86/91 - - - A4R43_RS38260 - PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 90/93 - - - 2-oxoacid dehydrogenase, acyltransferase, Amycolatopsis orientalis A4R43_RS38265 322 alpha/beta hydrolase - - - (AFI57004.1); 90/93 A4R43_RS38270 251 thioesterase thioesterase, Amycolatopsis orientalis (AFI57003.1); 95/98 - - - A4R43_RS38275 471 acyl-CoA carboxylase subunit beta propionyl-CoA carboxylase, Amycolatopsis orientalis (AFI57002.1); 97/98 - - - A4R43_RS38280 304 PAC2 family protein hypothetical protein, Amycolatopsis orientalis (AFI57001.1); 97/97 - - - SDR family NAD(P)-dependent A4R43_RS38285 247 short chain dehydrogenase, Amycolatopsis orientalis (AFI56999.1); 97/98 - - - oxidoreductase A4R43_RS38290 243 FadR family transcriptional regulator regulatory protein, Amycolatopsis orientalis (AFI56998.1); 89/93 - - -

37 Table S18. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces armeniacus ATCC 15676 (CP031320.1)

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog LacI family transcriptional regulator, Streptomyces sp. CNH287 DVA86_31825 380 LacI family transcriptional regulator - - - (WP_037760459.1); 81/84 sugar ABC transporter permease, Streptomyces sp. CNH287 DVA86_31830 326 sugar ABC transporter permease - - - (WP_027750470.1); 89/92 carbohydrate ABC transporter permease, Streptomyces sp. CNH287 DVA86_31835 300 carbohydrate ABC transporter permease - - - (WP_051262793.1); 88/93 extracellular solute-binding protein, Streptomyces sp. Z26 (WP_121516363.1); DVA86_31840 444 extracellular solute-binding protein - - - 82/89 DVA86_31845 334 ADP-ribosylglycohydrolase family protein crystallin, Streptomyces rimosus (WP_033027683.1); 87/91 - - - DVA86_31855 1954 polyketide synthase ChlA1, Streptomyces antibioticus (AAZ77693.1); 61/71 - - - DVA86_31860 182 Diels-Alderase hypothetical protein, Actinocrispum wychmicini (WP_132116074.1); 41/52 AbyU AbsU AbmU SDR family NAD(P)-dependent SDR family oxidoreductase, Pseudonocardia acaciae (WP_028921087.1); DVA86_31865 262 - - - oxidoreductase 66/76 class I SAM-dependent methyltransferase, Streptomyces aureocirculatus DVA86_31870 433 class I SAM-dependent methyltransferase - - - (WP_030566749.1); 73/83 NAD-dependent epimerase/dehydratase DVA86_31875 258 ChlC5, Streptomyces antibioticus (AAZ77680.1); 53/68 - - - family protein DUF1205 domain-containing protein, Micromonospora sp. HK10 DVA86_31880 404 DUF1205 domain-containing protein - - - (WP_046564311.1); 55/66 DUF1205 domain-containing protein, Micromonospora sp. HK10 DVA86_31885 415 DUF1205 domain-containing protein - - - (WP_046564311.1); 49/64

38 Table S19. Predicted functions of ORFs surrounding AbyU homolog from Amycolatopsis sp. CA-126428 (NZ_PPHF01000036).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog 139 C2L58_RS10660 PKS I type I polyketide synthase, Actinokineospora inagensis (WP_084467521.1); 65/73 - - - 8 DHA2 family efflux MFS transporter permease subunit, Actinokineospora inagensis C2L58_RS10665 171 Diels-Alderase AbyU AbsU AbmU (WP_084467520.1); 76/85 DHA2 family efflux MFS transporter permease subunit, Actinokineospora inagensis C2L58_RS10670 468 MFS transporter - - - (WP_084467520.1); 85/91 C2L58_RS10675 173 hypothetical protein hypothetical protein, Actinokineospora inagensis (WP_026422675.1); 68/78 - - - C2L58_RS10680 - hypothetical protein type I polyketide synthase, Actinokineospora inagensis (WP_051385696.1); 74/82 - - -

39 Table S20. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces caatingaensis CMAA 1322 (NZ_LFXA01000017).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog MarR family transcriptional MarR family transcriptional regulator, Streptomyces griseocarneus AC230_RS23505 161 - - - regulator (WP_121798617.1); 70/79 respiratory nitrate reductase respiratory nitrate reductase subunit gamma, Streptomyces sp. NRRL B-1347 AC230_RS23510 228 - - - subunit gamma (WP_078868664.1); 73/83 nitrate reductase molybdenum nitrate reductase molybdenum cofactor assembly chaperone, Streptomyces orinoci AC230_RS23515 192 - - - cofactor assembly chaperone (WP_109280517.1); 71/79 AC230_RS23520 527 nitrate reductase subunit beta nitrate reductase subunit beta, Streptomyces orinoci (WP_109280530.1); 84/89 - - - AC230_RS23525 - nitrate reductase subunit alpha nitrate reductase subunit alpha, Streptomyces orinoci (WP_109280516.1); 84/89 - - - AC230_RS23530 871 M4 family peptidase M4 family peptidase, Streptomyces olivoreticuli (WP_116215423.1); 58/69 - - - DegT/DnrJ/EryC1/StrS family DegT/DnrJ/EryC1/StrS aminotransferase, Streptomyces rimosus subsp. rimosus AC230_RS23535 426 - - - aminotransferase ATCC 10970 (ELQ83841.1); 82/88 AC230_RS30460 335 hypothetical protein hypothetical protein, Streptomyces rimosus (WP_050503688.1); 68/75 - - - AC230_RS23545 77 hypothetical protein acyl carrier protein, Streptomyces rimosus (WP_078897713.1); 80/88 - - - (2,3-dihydroxybenzoyl)adenylate (2,3-dihydroxybenzoyl)adenylate synthase, Streptomyces rimosus AC230_RS23550 551 - - - synthase (WP_053801678.1); 74/79 AC230_RS23555 263 thioesterase thioesterase, Streptomyces rimosus (WP_030371682.1); 62/71 - - - AC230_RS23560 397 FAD-dependent oxidoreductase FAD-dependent oxidoreductase, Streptomyces rimosus (WP_030670919.1); 81/88 - - - AC230_RS23565 966 type I polyketide synthase type I polyketide synthase, Streptomyces rimosus (WP_050508728.1); 74/80 - - - CGNR zinc finger domain- CGNR zinc finger domain-containing protein, Streptomyces sp. NRRL F-5755 AC230_RS23570 171 - - - containing protein (WP_053700243.1); 72/83 AC230_RS23575 480 MFS transporter MFS transporter, Streptomyces sp. AM-2504 (WP_131121744.1); 74/83 - - - pyridoxal-phosphate dependent pyridoxal-phosphate dependent enzyme, Streptomyces rimosus (WP_079027570.1); AC230_RS23580 348 - - - enzyme 60/74 AC230_RS23585 217 serine acetyltransferase serine acetyltransferase, Streptomyces albus (WP_060729303.1); 68/79 - - - AC230_RS23590 175 Diels-Alderase hypothetical protein, Streptomyces rimosus (WP_033030402.1); 71/79 AbyU AbsU AbmU AC230_RS23595 435 tetratricopeptide hypothetical protein, Streptomyces rimosus (WP_003980475.1); 64/73 - - - iron ABC transporter, Streptomyces rimosus subsp. pseudoverticillatus AC230_RS23600 320 iron ABC transporter - - - (KOT92518.1); 73/81 AC230_RS23605 344 iron ABC transporter permease iron ABC transporter permease, Kribbella sp. YM53 (WP_131512197.1); 60/76 - - - ABC transporter substrate- AC230_RS23610 330 hypothetical protein, Streptomyces rimosus (WP_053801671.1); 60/70 - - - binding protein AC230_RS23620 455 hypothetical protein hypothetical protein, Streptomyces mobaraensis (WP_004952143.1); 70/75 - - - AC230_RS23625 69 hypothetical protein - - - -

40 AC230_RS23630 397 argininosuccinate synthase argininosuccinate synthase, Streptomyces mobaraensis (WP_004952138.1); 94/97 - - - AC230_RS23635 477 argininosuccinate argininosuccinate lyase, Streptomyces mobaraensis (WP_004952137.1); 94/95 - - - TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Streptomyces orinoci (WP_109278895.1); AC230_RS23640 182 - - - regulator 88/91 AC230_RS23645 519 MFS transporter MFS transporter, Streptomyces cinnamoneus (WP_099197714.1); 85/91 - - - AC230_RS23650 276 alpha/beta fold hydrolase alpha/beta fold hydrolase, Streptomyces luteoverticillatus (WP_126913376.1); 88/93 - - - 1-acyl-sn-glycerol-3-phosphate 1-acyl-sn-glycerol-3-phosphate acyltransferase, Streptomyces mobaraensis AC230_RS23655 225 - - - acyltransferase (WP_004955746.1); 93/96 glycerophosphodiester glycerophosphodiester phosphodiesterase, Streptomyces mobaraensis AC230_RS23660 394 - - - phosphodiesterase (WP_040892776.1); 87/91

41 Table S21. Predicted functions of ORFs in potential BGC from Streptomyces cattleya DSM 46488 (NC_017586.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog DUF1360 domain-containing protein, Actinomadura sp. WAC 06369 SCATT_RS00545 164 DUF1360 domain-containing protein - - - (RSN60148.1); 59/69 dihydrolipoyl dehydrogenase, Streptomyces populi (WP_103553595.1); SCATT_RS00550 466 dihydrolipoyl dehydrogenase - - - 85/93 SCATT_RS00555 90 hypothetical protein hypothetical protein, Streptomyces olivaceus (WP_031047094.1); 76/82 - - - LLM class flavin-dependent SCATT_RS00560 393 monooxygenase, Streptomyces olivaceus (AOW90810.1); 95/98 - - - oxidoreductase SDR family NAD(P)-dependent oxidoreductase, Streptomyces SCATT_RS00565 277 SDR family oxidoreductase - - - varsoviensis (WP_030882095.1); 95/97 hypothetical protein BC342_34615, Streptomyces olivaceus SCATT_RS35820 101 hypothetical protein - - - (AOW90812.1); 79/78 crotonyl-CoA carboxylase/reductas, Streptomyces olivaceus SCATT_RS00570 454 crotonyl-CoA carboxylase/reductase - - - (WP_070390081.1); 97/98 IS3 family transposase, Streptomyces sp. AmelKG-D3 SCATT_RS00575 109 integrase - - - (WP_099217416.1); 86/89 LuxR family transcriptional regulator, Streptomyces varsoviensis SCATT_RS00580 925 helix-turn-helix transcriptional regulator - - - (WP_030882089.1); 89/93 SCATT_RS00585 75 hypothetical protein - - - - SCATT_RS00590 408 cytochrome P450 cytochrome P450, Streptomyces varsoviensis (WP_078643428.1); 91/95 - - - SCATT_RS00595 339 thioesterase thioesterase, Streptomyces varsoviensis (WP_078643426.1); 90/94 - - - nuclear transport factor 2 family protein, Streptomyces varsoviensis SCATT_RS00600 158 nuclear transport factor 2 family protein - - - (WP_030882078.1); 90/94 NAD(P)-dependent oxidoreductase, Streptomyces varsoviensis SCATT_RS00605 280 NAD(P)-dependent oxidoreductase - - - (WP_030882077.1); 93/97 hypothetical protein, Streptomyces varsoviensis (WP_030882074.1); SCATT_RS00610 140 Diels-Alderase AbyU AbsU AbmU 96/98 nuclear transport factor 2 family protein, Streptomyces olivaceus SCATT_RS00615 133 nuclear transport factor 2 family protein - - - (WP_070390078.1); 91/96 cytochrome P450, Streptomyces sp. E5N91 SAI-083 (WP_123627589.1); SCATT_RS00620 416 cytochrome P450 - - - 93/96 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. E5N91 SCATT_RS00625 6125 PKS I - - - SAI-083 (WP_123627588.1); 92/94 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. E5N91 SCATT_RS00630 4349 PKS I - - - SAI-083 (WP_123627587.1); 90/93 pyridoxamine 5'-phosphate oxidase pyridoxamine 5'-phosphate oxidase family protein, Streptomyces sp. SCATT_RS00635 172 - - - family protein E5N91 SAI-083 (WP_123627586.1); 90/94 type I polyketide synthase, Streptomyces iranensis (WP_044580009.1); SCATT_RS00640 3931 PKS I - - - 92/95 type I polyketide synthase, Streptomyces iranensis (WP_044580010.1); SCATT_RS00645 1345 PKS I - - - 91/94

42 SCATT_RS37820 21 gamma-butyrolactone receptor protein - - - - SCATT_RS37825 123 hypothetical protein - - - - MBL fold metallo-hydrolase, Streptomyces viridosporus SCATT_RS00655 161 MBL fold metallo-hydrolase - - - (WP_081235511.1); 96/98 galactose mutarotase, Streptomyces sp. Amel2xE9 (WP_037724950.1); SCATT_RS00660 377 galactose mutarotase - - - 75/82 TetR/AcrR family transcriptional regulator, Streptomyces sp. ADI95-16 SCATT_RS00665 202 TetR/AcrR family transcriptional regulator - - - (WP_123083105.1); 46/68 SCATT_RS00675 366 oxidoreductase oxidoreductase, Streptomyces hygroscopicus (WP_030822548.1); 93/95 - - - SCATT_RS00680 59 hypothetical protein - - - - IS5/IS1182 family transposase, Streptomyces sp. WAC 01438 SCATT_RS00685 256 IS5/IS1182 family transposase - - - (AZM62328.1); 96/98 SCATT_RS00690 79 hypothetical protein - - - - SCATT_RS00695 416 hypothetical protein hypothetical protein, Kitasatospora mediocidica (WP_035804847.1); 79/85 - - - TnsA-like heteromeric transposase endonuclease subunit, Streptomyces SCATT_RS00700 109 hypothetical protein - - - sp. 4121.5 (WP_100841043.1); 77/79 SCATT_RS00710 228 dipeptidase dipeptidase, Streptomyces sp. CNH287 (WP_027749012.1); 87/92 - - - NADP-dependent oxidoreductase, Streptomyces sp. NRRL S-340 SCATT_RS00715 317 NADP-dependent oxidoreductase - - - (WP_037861743.1); 86/91 SDR family NAD(P)-dependent SDR family oxidoreductase, Streptomyces sp. 840.1 (WP_123531887.1); SCATT_RS00720 136 - - - oxidoreductase 86/93 SDR family oxidoreductase, Streptomyces sp. 840.1 (WP_123531928.1); SCATT_RS00725 236 SDR family oxidoreductase - - - 92/95 LysR family transcriptional regulator, Streptomyces sp. 840.1 SCATT_RS00730 307 LysR family transcriptional regulator - - - (WP_123531885.1); 92/94 NAD-dependent epimerase/dehydratase family protein, Streptomyces sp. SCATT_RS00735 56 hypothetical protein - - - H23 (WP_134653989.1); 96/100 NAD-dependent epimerase/dehydratase family protein, Streptomyces SCATT_RS00740 83 hypothetical protein - - - natalensis (WP_044366192.1); 53/65 NAD(P)/FAD-dependent oxidoreductase, Streptomyces scabrisporus SCATT_RS00745 503 NAD(P)/FAD-dependent oxidoreductase - - - (WP_020548648.1); 52/65 CGNR zinc finger domain-containing zf-CGNR multi-domain protein, Streptomyces sp. MspMP-M5 SCATT_RS00750 194 - - - protein (WP_026247789.1); 95/96 major facilitator superfamily MFS_1, Streptomyces iranensis SCATT_RS00755 481 MFS transporter - - - (CDR01235.1); 96/97

43 Table S22. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces sp. CB03911 (NZ_LWLA01000047).

Size Aby Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Abs homolog (aa) homolog homolog LLM class flavin- LLM class flavin-dependent oxidoreductase, Streptacidiphilus sp. DSM 106435 A6A07_RS37465 354 - - AbmE2 dependent oxidoreductase (WP_111490410.1); 95/97 acyltransferase domain-containing protein, Streptacidiphilus sp. DSM 106435 A6A07_RS37470 1094 PKS I AbyB3 AbsB3 AbmB3 (WP_111490411.1); 94/95 SDR family NAD(P)-dependent oxidoreductase, Streptacidiphilus sp. DSM 106435 A6A07_RS37475 2188 PKS I AbyB2 AbsB2 AbmB2 (WP_114914558.1); 91/93 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptacidiphilus sp. DSM 106435 A6A07_RS37480 344 AbyA1 AbsA1 AbmA1 family protein (WP_111492779.1); 97/97 A6A07_RS37485 126 Diels-Alderase hypothetical protein, Streptacidiphilus sp. DSM 106435 (WP_111492780.1); 92/96 AbyU AbsU AbmU A6A07_RS37490 437 cytochrome P450 cytochrome P450, Streptacidiphilus sp. DSM 106435 (WP_111492778.1); 98/99 AbyX/AbyV AbsV/AbsX AbmV A6A07_RS37495 70 ferredoxin ferredoxin, Streptacidiphilus sp. DSM 106435 (WP_111492777.1); 88/94 - AbsG2/AbsG1 AbmG A6A07_RS37500 395 acyltransferase acyltransferase, Streptacidiphilus sp. DSM 106435 (WP_111492775.1); 92/94 - AbsI - A6A07_RS37505 331 aldo/keto reductase aldo/keto reductase, Streptacidiphilus sp. DSM 106435 (WP_111492774.1); 98/98 - AbsJ AbmJ A6A07_RS37510 480 MFS transporter MFS transporter, Streptacidiphilus sp. DSM 106435 (WP_114914554.1); 97/97 AbyD AbsD AbmD LLM class flavin- LLM class flavin-dependent oxidoreductase, Kutzneria buriramensis A6A07_RS37515 422 - - - dependent oxidoreductase (WP_116181636.1); 56/67 LLM class flavin- LLM class flavin-dependent oxidoreductase, Streptomyces sp. Ru71 A6A07_RS37520 353 - - - dependent oxidoreductase (WP_103783148.1); 49/57 LuxR family transcriptional LuxR family transcriptional regulator, Streptacidiphilus sp. DSM 106435 A6A07_RS37525 601 AbyH - AbmH regulator (WP_114914553.1); 91/93 A6A07_RS37530 94 acyltransferase acyltransferase, Streptacidiphilus sp. DSM 106435 (WP_111494374.1); 95/97 AbyA4 AbsA4 AbmA4 A6A07_RS37535 370 alpha/beta hydrolase alpha/beta hydrolase, Streptacidiphilus sp. DSM 106435 (WP_111494372.1); 96/97 AbyA5 AbsA5 AbmA5 AfsR/SARP family AfsR/SARP family transcriptional regulator, Streptacidiphilus sp. DSM 106435 A6A07_RS37540 296 AbyI - AbmI transcriptional regulator (WP_111494370.1); 96/97 A6A07_RS37545 279 thioesterase thioesterase, Streptacidiphilus sp. DSM 106435 (WP_111494376.1); 89/91 AbyT AbsN AbmT SDR family NAD(P)-dependent oxidoreductase, Streptacidiphilus sp. DSM 106435 A6A07_RS37550 6420 PKS I AbyB1 AbsB1 AbmB1 (WP_114914725.1); 90/92 A6A07_RS37555 76 hypothetical protein hypothetical protein, Streptacidiphilus sp. DSM 106435 (WP_114914550.1); 68/73 - - - HAD-IIIC family HAD-IIIC family phosphatase, Streptacidiphilus sp. DSM 106435 A6A07_RS37560 639 AbyA2 AbsA2 AbmA2 phosphatase (WP_111488988.1); 94/96 A6A07_RS37565 82 acyl carrier protein acyl carrier protein, Streptacidiphilus sp. DSM 106435 (WP_111488990.1); 93/95 AbyA3 AbsA3 AbmA3 NADPH-dependent FMN NADPH-dependent FMN reductase, Streptacidiphilus sp. DSM 106435 A6A07_RS37570 180 AbyZ AbsH1 AbmZ reductase (WP_111488992.1); 94/96

44 Table S23. Predicted functions of ORFs in potential BGC from Streptomyces sp. E5N91 SAI-083 (NZ_RJKF01000001.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog SDR family NAD(P)-dependent SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. E5N298 EDC84_RS34320 235 - - - oxidoreductase (WP_121703707.1); 99/98 EDC84_RS34325 67 hypothetical protein conserved hypothetical protein, Streptomyces lividans TK24 (EFD71066.1); 99/98 - - - LysR family transcriptional regulator, Streptomyces sp. M1013 (WP_076972954.1); EDC84_RS34330 301 LysR family transcriptional regulator - - - 99/99 NAD(P)H-dependent oxidoreductase, Streptomyces sp. CS113 EDC84_RS34335 187 NAD(P)H-dependent oxidoreductase - - - (WP_087805165.1); 98/99 helix-turn-helix transcriptional TetR/AcrR family transcriptional regulator, Streptomyces sp. M1013 EDC84_RS34340 234 - - - regulator (WP_076972906.1); 97/97 LacI family transcriptional regulator, Streptomyces sp. M1013 (OMI91275.1); EDC84_RS34345 344 LacI family transcriptional regulator - - - 99/100 EDC84_RS34350 131 thioredoxin thioredoxin, Streptomyces canus (WP_059296951.1); 99/100 - - - NAD(P)/FAD-dependent NAD(P)/FAD-dependent oxidoreductase, Streptomyces sp. E5N298 EDC84_RS34355 477 - - - oxidoreductase (WP_121703708.1); 99/99 EDC84_RS34360 218 peptide deformylase peptide deformylase, Streptomyces sp. E5N298 (WP_121703724.1); 96/98 - - - tetratricopeptide repeat protein, Streptomyces sp. S10(2018) (WP_127893298.1); EDC84_RS34365 115 tetratricopeptide repeat protein - - - 97/100 EDC84_RS34370 321 pirin family protein pirin family protein, Streptomyces canus (WP_059296947.1); 98/98 - - - EDC84_RS34375 107 hypothetical protein transposase, Streptomyces viridosporus ATCC 14672 (EFE71945.1); 64/68 - - - EDC84_RS34380 511 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces parvulus (WP_114532779.1); 98/98 - - - MerR family transcriptional regulator, Streptomyces parvulus (WP_114532776.1); EDC84_RS34385 - MerR family transcriptional regulator - - - 97/98 EDC84_RS34390 - IS701 family transposase SRSO17 transposase, Streptomyces sp. 75 (REE37585.1); 84/92 - - - methyltransferase domain- methyltransferase domain-containing protein, Streptomyces olivaceus EDC84_RS34395 281 - - - containing protein (WP_070390074.1); 97/98 acyltransferase domain-containing EDC84_RS34400 1365 type I polyketide synthase, Streptomyces olivaceus (WP_070390075.1); 95/96 - - - protein SDR family NAD(P)-dependent EDC84_RS34405 3938 type I polyketide synthase, Streptomyces olivaceus (WP_031033161.1); 97/97 - - - oxidoreductase pyridoxamine 5'-phosphate oxidase pyridoxamine 5'-phosphate oxidase family protein, Streptomyces olivaceus EDC84_RS34410 117 - - - family protein (WP_031033163.1); 99/99 SDR family NAD(P)-dependent EDC84_RS34415 4377 type I polyketide synthase, Streptomyces cattleya (WP_014140914.1); 90/93 - - - oxidoreductase SDR family NAD(P)-dependent EDC84_RS34420 6126 type I polyketide synthase, Streptomyces olivaceus (WP_070390077.1); 96/97 - - - oxidoreductase EDC84_RS34425 420 cytochrome P450 cytochrome P450, Streptomyces olivaceus (WP_031047118.1); 97/98 - - - nuclear transport factor 2 family nuclear transport factor 2 family protein, Streptomyces olivaceus EDC84_RS34430 134 - - - protein (WP_070390078.1); 95/97

45 EDC84_RS34435 141 Diels-Alderase hypothetical protein BC342_34580, Streptomyces olivaceus (AOW90806.1); 98/99 AbyU AbsU AbmU NAD(P)-dependent oxidoreductase, Streptomyces olivaceus (WP_031047111.1); EDC84_RS34440 281 NAD(P)-dependent oxidoreductase - - - 98/98 nuclear transport factor 2 family nuclear transport factor 2 family protein, Streptomyces olivaceus EDC84_RS34445 158 - - - protein (WP_031047108.1); 97/98 EDC84_RS34450 332 thioesterase thioesterase, Streptomyces varsoviensis (WP_078643426.1); 85/90 - - - EDC84_RS34455 409 cytochrome P450 cytochrome P450, Streptomyces varsoviensis (WP_078643428.1); 90/94 - - - LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces cattleya EDC84_RS34460 394 - - - oxidoreductase (WP_014140896.1); 96/98 EDC84_RS34465 278 SDR family oxidoreductase SDR family oxidoreductase, Streptomyces cattleya (WP_014140897.1); 94/96 - - - EDC84_RS34470 145 hypothetical protein hypothetical protein BC342_34615, Streptomyces olivaceus (AOW90812.1); 97/97 - - - crotonyl-CoA carboxylase/reductase, Streptomyces olivaceus (WP_070390081.1); EDC84_RS34475 455 crotonyl-CoA carboxylase/reductase - - - 99/98 helix-turn-helix transcriptional helix-turn-helix transcriptional regulator, Streptomyces olivaceus EDC84_RS34480 926 - - - regulator (WP_070387930.1); 93/96

46 Table S24. Predicted functions of ORFs in potential BGC from Micromonospora eburnean DSM 44814 (NZ_FMHY01000002.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog SDR family NAD(P)-dependent GA0070604_RS20550 1339 type I polyketide synthase, Streptomyces sp. RTd22 (WP_079152145.1); 45/57 - - - oxidoreductase GA0070604_RS20555 77 hypothetical protein acetylhydrolase, Micromonospora sp. CB01531 (WP_073835454.1); 71/80 - - - methyltransferase, Candidatus Streptomyces philanthi (WP_114021299.1); GA0070604_RS20560 253 hypothetical protein - - - 67/81 GA0070604_RS20565 437 cytochrome P450 cytochrome P450, Streptomyces oceani (WP_070196845.1); 47/62 - - - ABC transporter ATP-binding ABC transporter ATP-binding protein, Streptomyces varsoviensis GA0070604_RS20570 578 - - - protein (WP_030881385.1); 68/83 ABC transporter ATP-binding ABC transporter ATP-binding protein, Streptomyces griseoplanus GA0070604_RS20575 652 - - - protein (WP_055589414.1); 70/80 DUF1205 domain-containing DUF1205 domain-containing protein, Streptomyces sp. LHW50302 GA0070604_RS20580 412 - - - protein (WP_114017411.1); 55/67 FAD-dependent oxidoreductase, Streptomyces sp. LHW50302 GA0070604_RS20585 506 hypothetical protein - - - (WP_114019176.1); 60/71 type I polyketide synthase, Micromonospora haikouensis (WP_091284722.1); GA0070604_RS20590 1759 type I polyketide synthase - - - 86/90 3-oxoacyl-ACP synthase, Micromonospora haikouensis (WP_091284724.1); GA0070604_RS20595 348 3-oxoacyl-ACP synthase - - - 83/93 GA0070604_RS20600 403 cytochrome P450 cytochrome P450, Candidatus Streptomyces philanthi (WP_114021298.1); 77/85 - - - GA0070604_RS20605 200 Diels-Alderase hypothetical protein, Streptomyces sp. LHW50302 (WP_114017401.1); 73/80 AbyU AbsU AbmU acyl transferase domain-containing protein, Actinomadura pelletieri DSM 43383 GA0070604_RS20610 1866 type I polyketide synthase - - - (RKS68196.1); 54/65 GA0070604_RS20615 3995 type I polyketide synthase ChlA5, Streptomyces antibioticus (AAZ77698.1); 57/68 - - - acyltransferase domain-containing protein, Candidatus Streptomyces philanthi GA0070604_RS20625 923 hypothetical protein - - - (WP_114025062.1); 66/77 acyltransferase domain-containing protein, Actinomadura pelletieri GA0070604_RS20630 498 hypothetical protein - - - (WP_121438117.1); 46/56 acyltransferase domain-containing protein, Streptomyces LHW50302 GA0070604_RS20635 160 hypothetical protein - - - (WP_114019184.1); 50/62 GA0070604_RS20640 492 hypothetical protein hypothetical protein, Actinomadura pelletieri (WP_121438116.1); 60/71 - - - 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Candidatus Streptomyces philanthi GA0070604_RS20645 344 - - - family protein (WP_114025060.1); 70/82 GA0070604_RS20650 330 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces armeniacus (AXK32423.1); 64/76 - - - AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Candidatus Streptomyces philanthi GA0070604_RS20655 258 - - - regulator (WP_114025055.1); 69/82 GA0070604_RS20660 263 thioesterase thioesterase, Actinomadura pelletieri (WP_121438108.1); 57/72 - - -

47 Table S25. Predicted functions of ORFs in abyssomicin BGC from Frankia sp. AvcI1 (NZ_LJFZ01000030.1 and NZ_LJFZ01000034).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog UK94_RS25170 496 MFS transporter MFS transporter, Frankia alni (WP_011605223.1); 99/99 AbyD AbsD AbmD ABC transporter substrate-binding ABC transporter substrate-binding protein, Frankia alni (WP_011605219.1); UK94_RS25175 552 AbyF1 AbsF1 AbmF1 protein 98/98 UK94_RS25180 306 ABC transporter permease ABC transporter permease, Frankia alni ACN14a (CAJ62730.1); 99/99 AbyF2 AbsF2 AbmF2 UK94_RS25185 262 ABC transporter permease ABC transporter permease, Frankia alni (WP_011605217.1); 98/98 AbyF3 AbsF3 AbmF3 ABC transporter ATP-binding UK94_RS25190 582 ABC transporter ATP-binding protein, Frankia alni (WP_050997164.1); 99/99 AbyF4 AbsF4 AbmF4 protein UK94_RS25195 396 cytochrome P450 cytochrome P450, Frankia alni (WP_011605215.1); 98/98 AbyX/AbyV AbsV AbmV UK94_RS25200 73 ferredoxin ferredoxin, Frankia alni (WP_011605214.1); 99/98 - AbsG1 AbmG UK94_RS25205 314 aldo/keto reductase aldo/keto reductase, Frankia alni (WP_011605213.1); 99/99 - AbsJ AbmJ UK94_RS25210 129 hypothetical protein hypothetical protein, Frankia alni (WP_011605212.1); 99/99 AbyU AbsU AbmU UK94_RS25215 951 LuxR family transcriptional regulator LuxR family transcriptional regulator, Frankia alni (WP_011605211.1); 99/99 AbyH - AbmH AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Frankia alni (WP_041939444.1); UK94_RS25220 256 AbyR - - regulator 99/99 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Frankia alni (WP_011605207.1); UK94_RS25225 344 AbyA1 AbsA1 AbmA1 protein 99/99 UK94_RS25230 74 acyl carrier protein hypothetical protein FRAAL4076, Frankia alni ACN14a (CAJ62718.1); 98/100 AbyA3 AbsA3 AbmA3 UK94_RS25235 252 acyltransferase acyltransferase, Frankia alni (WP_011605205.1); 99/99 AbyA4 AbsA4 AbmA4 UK94_RS25240 360 alpha/beta hydrolase alpha/beta hydrolase, Frankia alni (WP_011605204.1); 99/99 AbyA5 AbsA5 AbmA5 UK94_RS25245 281 thioesterase thioesterase, Frankia alni (WP_011605203.1); 99/99 AbyT AbsN AbmT UK94_RS26870 4436 PKS I type I polyketide synthase, Frankia alni ACN14a (CAJ62714.1); 99/98 AbyB1 AbsB1 AbmB1 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// UK94_RS26865 3490 PKS I type I polyketide synthase, Frankia alni (WP_011605201.1); 99/99 AbyB2 AbsB2 AbmB2 acyltransferase domain-containing protein, Frankia alni (WP_011605200.1); UK94_RS26860 1042 PKS I AbyA3 AbsB3 AbmB3 99/99 UK94_RS26855 629 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Frankia alni (WP_011605199.1); 99/99 AbyA2 AbsA2 AbmA2

48 Table S26. Predicted functions of ORFs surrounding AbyU homolog from Actinomadura fibrosa LMG 29177 (CAACUY010000117.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog acyltransferase domain-containing Erythronolide synthase, modules 1 and 2, Streptomyces sp. M56 (AUA16058.1); E1300_RS30030 1651 - - - protein 50/61 E1300_RS30035 520 multicopper oxidase family protein copper oxidase, Streptomyces sp. NRRL S-813 (WP_030177947.1); 69/76 - - - E1300_RS30040 158 hypothetical protein hypothetical protein, Amycolatopsis taiwanensis (WP_052372290.1); 36/55 - - - E1300_RS30045 94 hypothetical protein hypothetical protein, Streptomyces sp. DvalAA-14 (WP_093739540.1); 43/55 - - - acyl-CoA carboxylase subunit beta, Streptomyces sp. DvalAA-14 E1300_RS30050 523 acyl-CoA carboxylase subunit beta - - - (WP_093739542.1); 82/88 E1300_RS30055 160 Diels-Alderase hypothetical protein, Streptomyces sp. NRRL F-525 (WP_033287247.1); 32/54 AbyU AbsU AbmU DHA2 family efflux MFS transporter DHA2 family efflux MFS transporter permease subunit, Rhodococcus sp. SMB37 E1300_RS30060 466 - - - permease subunit (WP_132471207.1); 51/66 MarR family transcriptional MarR family transcriptional regulator, Streptomyces formicae E1300_RS30065 192 - - - regulator (WP_098245770.1); 43/63 E1300_RS30070 496 hypothetical protein hypothetical protein, Streptomyces agglomeratus (WP_069929832.1); 53/68 - - - E1300_RS30075 323 hypothetical protein - - - - E1300_RS30080 279 hypothetical protein Phage integrase family protein, Actinomadura echinospora (SEF92328.1); 69/79 - - - E1300_RS30085 160 NUDIX domain-containing protein hypothetical protein, Actinokineospora inagensis (WP_035306982.1); 50/66 - - - DUF2326 domain-containing NUDIX domain-containing protein, Nonomuraea wenchangensis E1300_RS30090 579 - - - protein (WP_091081257.1); 62/76 E1300_RS30095 84 hypothetical protein - - - -

49 Table S27. Predicted functions of ORFs in abyssomicin BGC from Frankia alni ACN14a (NC_008278.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog FRAAL_RS17820 629 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Frankia sp. AvcI1 (WP_055752028.1); 99/99 AbyA2 AbsA2 AbmA2 acyltransferase domain-containing acyltransferase domain-containing protein, Frankia sp. AvcI1 FRAAL_RS17825 1042 AbyB3 AbsB3 AbmB3 protein (WP_055752029.1); 99/99 FRAAL_RS17830 3486 PKS I type I polyketide synthase, Frankia sp. AvcI1 (WP_055752030.1); 99/99 AbyB2 AbsB2 AbmB2 FRAAL_RS32455 hypothetical protein type I polyketide synthase, Frankia sp. AvcI1 (WP_095213022.1); 99/99 FRAAL_RS32460 polyketide synthase type I polyketide synthase, Frankia sp. AvcI1 (WP_095213022.1); 99/99 FRAAL_RS32465 hypothetical protein type I polyketide synthase, Frankia sp. AvcI1 (WP_095213022.1); 99/98 FRAAL_RS31810 hypothetical protein type I polyketide synthase, Frankia sp. AvcI1 (WP_095213022.1); 100/100 FRAAL_RS31815 polyketide synthase type I polyketide synthase, Frankia sp. AvcI1 (WP_095213022.1); 99/99 FRAAL_RS31820 hypothetical protein type I polyketide synthase, Frankia sp. AvcI1 (WP_095213022.1); 97/96 FRAAL_RS31825 hypothetical protein type I polyketide synthase, Frankia sp. AvcI1 (WP_095213022.1); 99/99 - AbyB1 AbsB1 AbmB1 FRAAL_RS31830 polyketide synthase AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 75/83 FRAAL_RS32470 3-ketoacyl-ACP synthase AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 60/69 FRAAL_RS31835 modular polyketide synthase BFAS4 AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 67/73 FRAAL_RS32475 hypothetical protein AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 68;76 FRAAL_RS31850 polyketide synthase AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 65/75 FRAAL_RS31855 hypothetical protein polyketide synthase, Microbispora sp. GKU 823 (WP_079314734.1); 57/70 FRAAL_RS31860 hypothetical protein polyketide synthase type I, Streptomyces sp. E14 (EFF94120.1); 78/83 FRAAL_RS17840 281 thioesterase thioesterase, Frankia sp. AvcI1 (WP_055751806.1); 99/99 AbyT AbsN AbmT FRAAL_RS17845 360 alpha/beta hydrolase alpha/beta hydrolase, Frankia sp. AvcI1 (WP_055751805.1); 99/99 AbyA5 AbsA5 AbmA5 FRAAL_RS17850 252 acyltransferase acyltransferase, Frankia sp. AvcI1 (WP_055751804.1); 99/99 AbyA4 AbsA4 AbmA4 acyl carrier protein, Streptomyces sp. NRRL F-5126 (WP_030912403.1); FRAAL_RS17855 74 acyl carrier protein AbyA3 AbsA3 AbmA3 53/73 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Frankia sp. AvcI1 FRAAL_RS17860 344 AbyA1 AbsA1 AbmA1 protein (WP_055751803.1); 99/99 AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Frankia sp. AvcI1 FRAAL_RS17865 256 AbyR - - regulator (WP_055751802.1); 99/98 LuxR family transcriptional regulator, Frankia sp. AvcI1 (WP_055751801.1); FRAAL_RS17870 951 LuxR family transcriptional regulator AbyH - AbmH 99/99 FRAAL_RS17875 129 Diels-Alderase hypothetical protein, Frankia sp. AvcI1 (WP_055751820.1); 99/99 AbyU AbsU AbmU

50 FRAAL_RS17880 341 aldo/keto reductase aldo/keto reductase, Frankia sp. AvcI1 (WP_055751800.1); 99/99 - AbsJ AbmJ FRAAL_RS17885 73 ferredoxin ferredoxin, Frankia sp. AvcI1 (WP_055751799.1); 99/98 - AbsG1 AbmG FRAAL_RS17890 396 cytochrome P450 cytochrome P450, Frankia sp. AvcI1 (WP_055751798.1); 98/98 AbyX AbsV AbmV ABC transporter ATP-binding protein, Frankia sp. AvcI1 (WP_095212991.1); FRAAL_RS17895 598 ABC transporter ATP-binding protein AbyF4 AbsF4 AbmF4 99/99 FRAAL_RS17900 262 ABC transporter permease ABC transporter permease, Frankia sp. AvcI1 (WP_055751819.1); 98/98 AbyF3 AbsF3 AbmF3 FRAAL_RS17905 337 ABC transporter permease ABC transporter permease, Frankia sp. AvcI1 (WP_063845354.1); 99/99 AbyF2 AbsF2 AbmF2 ABC transporter substrate-binding ABC transporter substrate-binding protein, Frankia sp. AvcI1 FRAAL_RS17910 552 AbyF1 AbsF1 AbmF1 protein (WP_055751795.1); 98/98 FRAAL_RS17915 497 MFS transporter MFS transporter, Frankia sp. AvcI1 (WP_055751794.1); 99/99 AbyD AbsD AbmD LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. AvcI1 FRAAL_RS17920 331 AbyE AbsE AbmE1 oxidoreductase (WP_055751793.1); 99/99 FRAAL_RS17925 373 cytochrome P450 cytochrome P450, Frankia sp. AvcI1 (WP_055751792.1); 99/99 AbyX/AbyV AbsX AbmV TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Frankia sp. AvcI1 FRAAL_RS17930 203 - AbsC2 - regulator (WP_055751791.1); 98/98

51 Table S28. Predicted functions of ORFs in abyssomicin BGC from Frankia discariae BCU110501 (NZ_KB891214 and NZ_KB891274).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. EAN1pec B056_RS0115515 392 AbyE AbsE AbmE1 oxidoreductase (WP_020461007.1); 94/95 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Frankia sp. EAN1pec B056_RS0115520 234 AbyC - AbmC regulator (WP_020461008.1); 94/96 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. EAN1pec B056_RS0115525 360 - - AbmE2 oxidoreductase (WP_020461009.1); 96/96 propionyl-CoA carboxylase subunit beta, Frankia sp. EI5c B056_RS0115530 499 hypothetical protein - - - (WP_066072904.1); 81/85 B056_RS0115535 70 hypothetical protein hypothetical protein, Frankia sp. EAN1pec (WP_041254286.1); 88/89 - - - B056_RS0115540 405 cytochrome P450 cytochrome P450, Frankia sp. EAN1pec (WP_020461012.1); 98/99 AbyX/AbyV AbsV/AbsX AbmV B056_RS0115545 1093 PKS I type I polyketide synthase, Frankia sp. EI5c (WP_083987208.1); 77/82 AbyB3 AbsB3 AbmB3 type I polyketide synthase, Frankia sp. EAN1pec (WP_020461014.1); B056_RS0115550 2276 PKS I AbyB2 AbsB2 AbmB2 90/92 type I polyketide synthase, Streptomyces sp. KhCrAH-43 B056_RS36660 - PKS I AbyB1 AbsB1 AbmB1 (WP_018522876.1); 60/67 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// type I polyketide synthase, Streptomyces sp. KhCrAH-43 B056_RS42215 - PKS I AbyB1 AbsB1 AbmB1 (WP_018522876.1); 60/67 B056_RS0132560 65 ferredoxin ferredoxin, Frankia sp. EI5c (WP_066073232.1); 92/96 AbyW AbsG2/AbsG1 AbmG B056_RS0132555 399 cytochrome P450 cytochrome P450, Frankia sp. EAN1pec (WP_020461016.1); 98/99 AbyV/AbyX AbsV/AbsX AbmV ABC transporter ATP-binding ABC transporter ATP-binding protein, Frankia sp. EAN1pec B056_RS0132550 564 AbyF4 AbsF4 AbmF4 protein (WP_049795952.1); 94/95 ABC transporter permease, Frankia sp. EAN1pec (WP_020461018.1); B056_RS0132545 288 ABC transporter permease AbyF3 AbsF3 AbmF3 93/94 ABC transporter permease, Frankia sp. EAN1pec (WP_020461019.1); B056_RS0132540 317 ABC transporter permease AbyF2 AbsF2 AbmF2 95/97 ABC transporter substrate- ABC transporter substrate-binding protein, Frankia sp. EAN1pec B056_RS0132535 547 AbyF1 AbsF1 AbmF1 binding protein (WP_020461020.1); 96/97 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. EAN1pec B056_RS0132530 347 AbyE AbsE AbmE1 oxidoreductase (WP_020461021.1); 99/99 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Frankia sp. B056_RS0132525 486 AbyD AbsD AbmD transporter permease subunit EAN1pec (WP_020461022.1); 99/99 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Frankia sp. EAN1pec B056_RS0132520 250 AbyC - AbmC regulator (WP_020461023.1); 99/99 B056_RS0132515 374 alpha/beta hydrolase alpha/beta hydrolase, Frankia sp. EAN1pec (WP_020461024.1); 95/95 AbyA5 AbsA5 AbmA5 B056_RS0132510 259 acyltransferase acyltransferase, Frankia sp. EAN1pec (WP_049795953.1); 98/100 AbyA4 AbsA4 AbmA4 B056_RS0132505 78 acyl carrier protein acyl carrier protein, Frankia sp. EI5c (WP_066073198.1); 92/94 AbyA3 AbsA3 AbmA3

52 HAD-IIIC family phosphatase, Streptomyces sp. KhCrAH-43 B056_RS0132500 658 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 (WP_018522892.1); 70/78 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Frankia sp. EAN1pec B056_RS0132495 348 AbyA1 AbsA1 AbmA1 family protein (WP_020461027.1); 99/100 RHS repeat protein + Diels- B056_RS0132490 1024 RHS repeat protein, Frankia sp. EAN1pec (WP_020461028.1); 95/95 AbyK+AbyU AbsU AbmU Alderase

53 Table S29. Predicted functions of ORFs in abyssomicin BGC from Frankia sp. EAN1pec (CP000820.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) LLM class flavin-dependent oxidoreductase, Frankia discariae Franean1_3465 386 luciferase family protein AbyE AbsE AbmE1 (WP_026239744.1);94/95 transcriptional regulator, TetR TetR/AcrR family transcriptional regulator, Frankia discariae Franean1_3466 245 AbyC - AbmC family (WP_020572516.1); 94/96 LLM class flavin-dependent oxidoreductase, Frankia discariae Franean1_3467 354 luciferase family protein - - AbmE2 (WP_018502788.1); 96/96 putative acetyl/propionyl CoA Franean1_3468 141 hypothetical protein, Frankia discariae (WP_018502789.1); 80/80 - - - carboxylase beta subunit Franean1_3469 100 hypothetical protein hypothetical protein, Frankia discariae (WP_018502790.1); 86/88 - - - Franean1_3470 404 cytochrome P450 cytochrome P450, Frankia discariae (WP_026239745.1); 98/99 AbyX/AbyV AbsV/AbsX AbmV Franean1_3471 1071 PKS I type I polyketide synthase, Frankia discariae (WP_026239746.1); 93/94 AbyB3 AbsB3 AbmB3 type I polyketide synthase, Streptomyces sp. 2131.1 (WP_093709984.1); Franean1_3472 4111 PKS I AbyB2 AbsB2 AbmB2 59/67 type I polyketide synthase, Streptomyces sp. 2131.1 (WP_093709985.1); Franean1_3473 4840 PKS I AbyB1 AbsB1 AbmB1 53/62 protein of unknown function Franean1_3474 64 Ferredoxin, Streptomyces fragilis (WP_108952945.1); 59/78 AbyW AbsG2/AbsG1 AbmG DUF1271 Franean1_3475 398 cytochrome P450 cytochrome P450, Frankia discariae (WP_018506032.1); 98/99 AbyV/AbyX AbsV/AbsX AbmV ABC transporter ATP-binding protein, Frankia discariae Franean1_3476 594 ABC transporter related AbyF4 AbsF4 AbmF4 (WP_051105801.1); 94/95 binding-protein-dependent Franean1_3477 287 transport systems inner ABC transporter permease, Frankia discariae (WP_026240411.1); 93/94 AbyF3 AbsF3 AbmF3 membrane component binding-protein-dependent Franean1_3478 316 transport systems inner ABC transporter permease, Frankia discariae (WP_018506029.1); 95/97 AbyF2 AbsF2 AbmF2 membrane component extracellular solute-binding ABC transporter substrate-binding protein, Frankia discariae Franean1_3479 546 AbyF1 AbsF1 AbmF1 protein family 5 (WP_018506028.1); 96/97 LLM class flavin-dependent oxidoreductase, Frankia discariae Franean1_3480 346 luciferase family protein AbyE AbsE AbmE1 (WP_018506027.1); 99/99 drug resistance transporter, DHA2 family efflux MFS transporter permease subunit, Frankia discariae Franean1_3481 845 AbyD AbsD AbmD EmrB/QacA subfamily (WP_018506026.1); 99/99 transcriptional regulator, TetR etR/AcrR family transcriptional regulator, Frankia discariae Franean1_3482 248 AbyC - AbmC family (WP_018506025.1); 94/94 Franean1_3483 373 conserved hypothetical protein alpha/beta hydrolase, Frankia discariae (WP_018506024.1); 95/95 AbyA5 AbsA5 AbmA5 catalytic domain of components Franean1_3484 294 of various dehydrogenase Acyltransferase, Frankia discariae (WP_026240410.1); 98/100 AbyA4 AbsA4 AbmA4 complexes acyl carrier protein, Streptomyces sp. NRRL WC-3725 Franean1_3485 77 hypothetical protein AbyA3 AbsA3 AbmA3 (WP_031029037.1); 80/88

54 HAD-IIIC family phosphatase, Frankia discariae (WP_018506021.1); Franean1_3486 142 conserved hypothetical protein AbyA2 AbsA2 AbmA2 84/87 Beta-ketoacyl-acyl-carrier-protein 3-oxoacyl-ACP synthase III family protein, Frankia discariae Franean1_3487 348 AbyA1 AbsA1 AbmA1 synthase I (WP_018506020.1); 99/100 YD repeat protein + Diels- Franean1_3488 1023 RHS repeat protein, Frankia discariae (WP_018506019.1); 94/95 AbyK+AbyU AbsU AbmU Alderase transcriptional regulator, SARP SARP family transcriptional regulator, Frankia discariae Franean1_3489 257 AbyI - AbmI family (WP_018506018.1); 98/99 LuxR family transcriptional helix-turn-helix transcriptional regulator, Frankia discariae Franean1_3490 950 AbyH - AbmH regulator (WP_018506017.1); 97/97

55 Table S30. Predicted functions of ORFs in abyssomicin BGC from Frankia sp. EI5c (NZ_LRTK01000008.1 and NZ_LRTK01000088.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog UG55_RS0738 142 Diels-Alderase hypothetical protein, Frankia sp. Cc1.17 (WP_071084438.1); 97/99 AbyU AbsU AbmU 0 UG55_RS0738 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Frankia sp. Cc1.17 349 AbyA1 AbsA1 AbmA1 5 protein (WP_071084440.1); 94/96 UG55_RS0739 672 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Frankia sp. Cc1.17 (WP_116287792.1); 87/89 AbyA2 AbsA2 AbmA2 0 UG55_RS0739 TetR/AcrR family transcriptional regulator, Frankia sp. Cc1.17 188 TetR family transcriptional regulator - - - 5 (WP_084132131.1); 94/96 UG55_RS0740 DHA2 family efflux MFS transporter DHA2 family efflux MFS transporter permease subunit, Frankia sp. Cc1.17 472 AbyD AbsD AbmD 0 permease subunit (WP_116287793.1); 95/97 UG55_RS0740 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. Cc1.17 336 AbyE AbsE AbmE1 5 oxidoreductase (WP_071084502.1); 93/96 UG55_RS0741 LuxR family transcriptional regulator, Frankia sp. Cc1.17 (WP_071084446.1); 1049 helix-turn-helix transcriptional regulator AbyH - AbmH 0 88/91 UG55_RS0741 AfsR/SARP family transcriptional 257 hypothetical protein, Frankia sp. Cc1.17 (WP_071084449.1); 89/94 AbyI - AbmI 5 regulator UG55_RS0742 76 acyl carrier protein acyl carrier protein, Frankia sp. Cc1.17 (WP_071084451.1); 97/97 AbyA3 AbsA3 AbmA3 0 UG55_RS0742 304 acyltransferase acyltransferase, Frankia sp. Cc1.17 (WP_084132123.1); 86/88 AbyA4 AbsA4 AbmA4 5 UG55_RS0743 359 alpha/beta hydrolase alpha/beta hydrolase, Frankia sp. Cc1.17 (WP_071084457.1) AbyA5 AbsA5 AbmA5 0 UG55_RS0743 - PKS I Contig edge PKS I PKS I PKS I 5 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// UG55_RS2361 - PKS I Contig edge PKS I PKS I PKS I 0 UG55_RS2360 65 ferredoxin ferredoxin, Streptomyces regensis (KMS84448.1); 59/81 - AbsG2 - 5 UG55_RS2360 399 cytochrome P450 cytochrome P450, Frankia sp. EAN1pec (WP_020461016.1); 90/93 AbyV/AbyX AbsV/AbsX AbmV 0 UG55_RS2359 ABC transporter ATP-binding protein, Frankia discariae (WP_051105801.1); 577 ABC transporter ATP-binding protein AbyF4 AbsF4 AbmF4 5 80/86 UG55_RS2359 287 ABC transporter permease ABC transporter permease, Frankia sp. Cc1.17 (WP_084131831.1); 81/88 AbyF3 AbsF3 AbmF3 0 UG55_RS2358 197 ABC transporter permease ABC transporter permease, Frankia discariae (WP_018506029.1); 79/88 AbyF2 AbsF2 AbmF2 5 UG55_RS2358 ABC transporter substrate-binding ABC transporter substrate-binding protein, Frankia discariae 547 AbyF1 AbsF1 AbmF1 0 protein (WP_018506028.1); 87/91 UG55_RS2357 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. BMG5.11 348 AbyE AbsE AbmE1 5 oxidoreductase (TCJ32075.1); 82/87 UG55_RS2357 491 DHA2 family efflux MFS transporter DHA2 family efflux MFS transporter permease subunit, Frankia sp. EAN1pec AbyD AbsD AbmD

56 0 permease subunit (WP_020461022.1); 90/94 UG55_RS2356 TetR/AcrR family transcriptional regulator, Frankia sp. Ea1.12 274 TetR/AcrR family transcriptional regulator AbyC - AbmC 5 (WP_112105117.1); 83/87 UG55_RS2356 362 alpha/beta hydrolase alpha/beta hydrolase, Frankia sp. EAN1pec (WP_020461024.1); 84/85 AbyA5 AbsA5 AbmA5 0 UG55_RS2355 246 acyltransferase acyltransferase, Frankia discariae (WP_026240410.1); 85/92 AbyA4 AbsA4 AbmA4 5 UG55_RS2355 acyl carrier protein, Streptomyces sp. NRRL WC-3725 (WP_031029037.1); 78 acyl carrier protein AbyA3 AbsA3 AbmA3 0 75/85 UG55_RS2354 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Frankia sp. EAN1pec 342 AbyA1 AbsA1 AbmA1 5 protein (WP_020461027.1); 87/91 UG55_RS2353 1080 RHS repeat protein RHS repeat protein, Frankia discariae (WP_018506019.1); 67/73 AbyK - - 5 UG55_RS2353 SARP family transcriptional regulator, Frankia discariae (WP_018506018.1); 258 activator protein AbyI - AbmI 0 90/93

57 Table S31. Predicted functions of ORFs in potential abyssomicin BGC from Frankia symbiont of Datisca glomerata (NC_015656.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) FSYMDG_RS09425 528 hypothetical protein acyltransferase, Amycolatopsis circi (WP_116201221.1); 55/68 - AbsI - FSYMDG_RS09430 68 ferredoxin ferredoxin, Frankia coriariae (KLL10399.1); 93/97 - AbsG1 AbmG FSYMDG_RS09435 274 thioesterase thioesterase, Frankia sp. AvcI1 (WP_055749039.1); 66/76 AbyT AbsN AbmT acyltransferase domain-containing protein, partial, Frankia symbiont of FSYMDG_RS24310 - PKS I PKS I PKS I PKS I Coriaria nepalensis (WP_131772417.1); 99/100 type I polyketide synthase, Frankia sp. BMG5.30 (WP_076843523.1); FSYMDG_RS25265 - PKS I PKS I PKS I PKS I 70/77 type I polyketide synthase, Streptomyces alfalfae (WP_076682132.1); FSYMDG_RS25270 - PKS I PKS I PKS I PKS I 55/62 acyltransferase domain-containing protein, partial, Frankia symbiont of FSYMDG_RS24325 - PKS I PKS I PKS I PKS I Coriaria nepalensis (WP_131772419.1); 100/100 type I polyketide synthase, Streptomyces alboviridis FSYMDG_RS24330 - PKS I PKS I PKS I PKS I (WP_032759890.1); 69/76 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia FSYMDG_RS24340 - PKS I PKS I PKS I PKS I symbiont of Coriaria nepalensis (WP_131772420.1); 99/99 type I polyketide synthase, Streptomyces exfoliatus FSYMDG_RS24345 - PKS I PKS I PKS I PKS I (WP_078626965.1); 57/67 acyltransferase domain-containing protein, Frankia symbiont of Coriaria FSYMDG_RS25275 - PKS I PKS I PKS I PKS I nepalensis (WP_131772422.1); 99/100 acyltransferase domain-containing protein, partial, Frankia symbiont of FSYMDG_RS24360 - PKS I PKS I PKS I PKS I Coriaria myrtifolia (WP_131773939.1); 99/100 FSYMDG_RS09445 345 alpha/beta hydrolase alpha/beta hydrolase, Frankia sp. BMG5.30 (ONH34857.1); 96/96 AbyA5 AbsA5 AbmA5 FSYMDG_RS09450 310 acyltransferase acyltransferase, Frankia sp. BMG5.30 (WP_076843553.1); 92/93 AbyA4 AbsA4 AbmA4 3-oxoacyl-ACP synthase III FSYMDG_RS09455 343 3-oxoacyl-ACP synthase, Frankia coriariae (KLL11317.1); 98/98 AbyA1 AbsA1 AbmA1 family protein monooxygenase FAD- FSYMDG_RS09460 569 hypothetical protein, Frankia sp. BMG5.30 (WP_076843525.1); 89/91 - - - binding protein LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. BMG5.30 FSYMDG_RS09465 356 - - AbmE2 oxidoreductase (WP_076843526.1); 96/98 FSYMDG_RS09470 230 cytochrome P450 cytochrome P450, Frankia coriariae (KLL11355.1); 99/100 AbyX/AbyV AbsV/AbsX AbmV IS66 family transposase, Frankia sp. ACN1ag (WP_055409628.1); FSYMDG_RS09475 478 IS66 family transposase - - - 82/85 FSYMDG_RS09480 155 cytochrome P450 cytochrome P450, Frankia coriariae (KLL11355.1); 99/99 AbyX/AbyV AbsX/AbsV AbmV AbsG1/AbsG FSYMDG_RS09485 83 ferredoxin ferredoxin, Frankia coriariae (KLL11356.1); 95/96 - AbmG 2 response regulator LuxR family transcriptional regulator, Frankia sp. BMG5.30 FSYMDG_RS09490 292 AbyH - AbmH transcription factor (WP_083731095.1); 92/92 FSYMDG_RS09495 202 TetR/AcrR family TetR/AcrR family transcriptional regulator, Frankia coriariae - AbsC2 -

58 transcriptional regulator (WP_052914596.1); 97/97 LuxR family transcriptional regulator, Frankia sp. BMG5.30 FSYMDG_RS09500 114 hypothetical protein - - - (WP_083731095.1); 77/80 AfsR/SARP family FSYMDG_RS09505 246 activator protein, Frankia sp. BMG5.30 (WP_076843528.1); 99//99 AbyI - AbmI transcriptional regulator FSYMDG_RS09510 328 aldo/keto reductase aldo/keto reductase, Frankia sp. BMG5.30 (WP_076843529.1); 98/98 - AbsJ AbmJ FSYMDG_RS09515 147 hypothetical protein hypothetical protein, Frankia sp. BMG5.30 (WP_076843530.1); 95/96 - - - FMN-binding glutamate FMN-binding glutamate synthase family protein, Frankia sp. BMG5.30 FSYMDG_RS09530 496 - - - synthase family protein (WP_076843531.1); 97/97 propionyl-CoA carboxylase propionyl-CoA carboxylase subunit beta, Frankia coriariae FSYMDG_RS09535 530 - - - subunit beta (KLL11331.1); 97/97 FSYMDG_RS09545 75 acyl carrier protein acyl carrier protein, Frankia sp. EI5c (WP_066064666.1); 65/76 AbyA3 AbsA3 AbmA3 HAD-IIIC family phosphatase, Frankia sp. BMG5.30 FSYMDG_RS09550 654 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 (WP_076843558.1); 98/98 FSYMDG_RS09555 498 MFS transporter MFS transporter, Microbispora triticiradicis (WP_117409462.1); 50/67 AbyD AbsD AbmD TetR/AcrR family TetR/AcrR family transcriptional regulator, Streptacidiphilus sp. DSM FSYMDG_RS09560 238 AbyC - AmbC transcriptional regulator 106435 (WP_111490402.1); 62/74 hypothetical protein FrCorBMG51_12000, Frankia coriariae FSYMDG_RS09565 125 Diels-Alderase AbyU AbsU AbmU (KLL11361.1); 96/100 NtaA/DmoA family FMN- LLM class flavin-dependent oxidoreductase, Paenibacillus sp. JDR-2 FSYMDG_RS09570 448 - - - dependent monooxygenase (WP_015846774.1); 60/76 ABC transporter ATP-binding ABC transporter ATP-binding protein, Frankia coriariae FSYMDG_RS09575 298 AbyF4 AbsF4 AbmF4 protein (WP_086055414.1); 92/93 ATP-binding cassette dipeptide/oligopeptide/nickel ABC transporter permease/ATP-binding FSYMDG_RS24370 674 AbyF3+AbyF4 AbsF3+AbsF4 AbmF3+AbmF4 domain-containing protein protein, Frankia coriariae (WP_047224248.1); 53/64 FSYMDG_RS09590 337 ABC transporter permease ABC transporter permease, Frankia coriariae (KLL11332.1); 97/98 AbmF2 AbsF2 AbmF2

59 Table S32. Predicted functions of ORFs in abyssomicin BGC from Frankia sp. Cc1.17 (MBLM01000080.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog LLM class flavin-dependent CC117_RS09725 371 luciferase, Frankia sp. Cc1.17 (OHV40281.1); 99/100 AbyE AbsE AbmE1 oxidoreductase ABC transporter ATP-binding CC117_RS09735 611 ABC transporter related, Frankia sp. EAN1pec (ABW12878.1); 84/87 AbyF4 AbsF4 AbmF4 protein CC117_RS09740 287 ABC transporter permease ABC transporter permease, Frankia sp. EAN1pec (WP_020461018.1); 85/91 AbyF3 AbsF3 AbmF3 CC117_RS09745 316 ABC transporter permease ABC transporter permease, Frankia discariae (WP_018506029.1); 92/96 AbyF2 AbsF2 AbmF2 ABC transporter substrate- ABC transporter substrate-binding protein, Frankia sp. EAN1pec (WP_020461020.1); CC117_RS09750 546 AbyF1 AbsF1 AbmF1 binding protein 88/92 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. EAN1pec CC117_RS09755 339 AbyE AbsE AbmE1 oxidoreductase (WP_020461021.1); 85/91 AfsR/SARP family CC117_RS09760 285 activator protein, Frankia sp. EI5c (WP_066073189.1); 83/89 AbyI - AbmI transcriptional regulator LuxR family transcriptional CC117_RS09765 921 helix-turn-helix transcriptional regulator, Frankia discariae (WP_018506017.1); 76/82 AbyH - AbmH regulator MetQ/NlpA family ABC ABC transporter substrate-binding protein, Frankia sp. EUN1f (WP_006542932.1); CC117_RS09770 277 transporter substrate-binding - - - 85/91 protein CC117_RS09775 199 ABC transporter permease ABC transporter permease, Frankia sp. EUN1f (WP_006542931.1); 91/93 - - - ATP-binding cassette ATP-binding cassette domain-containing protein, Frankia sp. EUN1f CC117_RS09780 360 AbyF4 AbsF4 AbmF4 domain-containing protein (WP_006542930.1); 86/90 FadR family transcriptional CC117_RS09785 334 FadR family transcriptional regulator, Frankia sp. EI5c (WP_083986722.1); 68/77 - - - regulator TetR/AcrR family TetR/AcrR family transcriptional regulator, Frankia sp. BMG5.36 (WP_071055116.1); CC117_RS09795 207 - - - transcriptional regulator 77/85 CC117_RS09800 476 MFS transporter MFS transporter, Frankia sp. EUN1h (OHV31341.1); 81/87 AbyD AbsD AbmD TetR/AcrR family CC117_RS09805 225 TetR/AcrR family transcriptional regulator, Frankia sp. EI5c (WP_066072908.1); 74/81 AbyC - AbmC transcriptional regulator CC117_RS34465 - PKS I type I polyketide synthase, Umezawaea tangerina (WP_106189546.1); 48/61 PKS I PKS I PKS I SDR family NAD(P)-dependent oxidoreductase, partial, Streptomyces coelicolor CC117_RS36135 - PKS I PKS I PKS I PKS I (WP_134115609.1); 61/72 type I polyketide synthase, Streptomyces sp. NBRC 109436 (WP_064455271.1); CC117_RS36140 - PKS I PKS I PKS I PKS I 59/70 SDR family NAD(P)-dependent oxidoreductase, Saccharopolyspora sp. 16K404 CC117_RS34485 - PKS I PKS I PKS I PKS I (WP_132624326.1); 56/67 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia symbiont of Coriaria CC117_RS36145 - PKS I PKS I PKS I PKS I nepalensis (WP_131772418.1); 68/71 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. MK-45 CC117_RS36150 - PKS I PKS I PKS I PKS I (WP_126395712.1); 54/63 CC117_RS09815 363 alpha/beta hydrolase alpha/beta hydrolase, Frankia sp. BMG5.30 (ONH34857.1); 66/73 AbyA5 AbsA5 AbmA5

60 CC117_RS09820 229 acyltransferase acyltransferase, Frankia coriariae (WP_086055410.1); 74/83 AbyA4 AbsA4 AbmA4 ABC transporter ATP-binding ATP-binding cassette domain-containing protein, Frankia sp. EI5c CC117_RS09825 337 AbyF4 AbsF4 AbmF4 protein (WP_066072919.1); 74/80 ABC transporter ATP-binding ABC transporter ATP-binding protein, Frankia sp. EAN1pec (WP_020461003.1); CC117_RS09830 356 AbyF4 AbsF4 AbmF4 protein 72/79 CC117_RS09835 278 ABC transporter permease ABC transporter permease, Frankia sp. EAN1pec (WP_020461004.1); 81/90 AbyF3 AbsF3 AbmF3 CC117_RS09840 324 ABC transporter permease ABC transporter permease, Frankia sp. EAN1pec (WP_020461005.1); 82/89 AbyF2 AbsF2 AbmF2 ABC transporter substrate- ABC transporter substrate-binding protein, Frankia sp. EAN1pec (WP_020461006.1); CC117_RS09845 523 AbyF1 AbsF1 AbmF1 binding protein 80/90 LLM class flavin-dependent CC117_RS09850 484 LLM class flavin-dependent oxidoreductase, Millisia brevis (WP_066905197.1); 53/66 - - - oxidoreductase DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Frankia symbiont of Datisca CC117_RS09855 481 transporter permease AbyD AbsD AbmD glomerata (WP_013873862.1); 80/86 subunit LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Actinokineospora auranticolor CC117_RS09860 354 AbyE AbsE AbmE1 oxidoreductase (WP_104480644.1); 60/71 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. EAN1pec CC117_RS09865 348 - - AbmE2 oxidoreductase (WP_020461009.1); 80/86 CC117_RS09870 1148 PKS I type I polyketide synthase, Actinomadura macra (WP_067456435.1); 58/67 AbyB1 AbsB1 AbmB1 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. NRRL S-31 CC117_RS09875 388 AbyA1 AbsA1 AbmA1 family protein (WP_030750290.1); 77/86 hypothetical protein CLV40_111123, Actinokineospora auranticolor (PPK66159.1); CC117_RS09880 131 Diels-Alderase AbyU AbsU AbmU 61/78 CC117_RS09885 184 Diels-Alderase hypothetical protein, Streptomyces sp. NRRL S-31 (WP_030750286.1); 57/68 AbyU AbsU AbmU CC117_RS09890 417 cytochrome P450 cytochrome P450, Streptomyces sp. NRRL S-31 (WP_030750284.1); 73/81 AbyV/AvyX AbsV/AbsX AbmV CC117_RS09895 64 ferredoxin ferredoxin-1, Streptomyces sp. CC71 (KYK09758.1); 60/75 - AbsG1 AbmG ABC transporter ATP-binding dipeptide ABC transporter ATP-binding protein, Frankia symbiont of Datisca CC117_RS09900 588 AbyF4 AbsF4 AbmF4 protein glomerata (WP_131768082.1); 77/82 ABC transporter permease subunit, Frankia symbiont of Datisca glomerata CC117_RS09905 316 ABC transporter permease AbyF3 AbsF3 AbmF3 (WP_131768081.1); 80/86 ABC transporter permease subunit, Frankia symbiont of Datisca glomerata CC117_RS09910 322 ABC transporter permease AbyF2 AbsF2 AbmF2 (WP_131768080.1); 84/92 ABC transporter substrate- ABC transporter substrate-binding protein, Frankia symbiont of Datisca glomerata CC117_RS09915 528 AbyF1 AbsF1 AbmF1 binding protein (WP_131768079.1); 79/86 TauD/TfdA family dioxygenase, Frankia symbiont of Datisca glomerata CC117_RS09920 307 taurine dioxygenase - - - (WP_131768078.1); 79/90 AfsR/SARP family AfsR/SARP family transcriptional regulator, Candidatus Streptomyces philanthi CC117_RS09925 260 AbyI - AbmI transcriptional regulator (WP_114025055.1); 52/68 CC117_RS09930 78 acyl carrier protein acyl carrier protein, Streptomyces olindensis (KDN76173.1); 61/74 AbyA3 AbsA3 AbmA3 CC117_RS09935 641 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Kutzneria buriramensis (WP_116181645.1); 64/75 AbyA2 AbsA2 AbmA2

61 Table S33. Predicted functions of ORFs in abyssomicin BGC from Frankia sp. Cc1.17 (NZ_MBLM01000112).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog CC117_RS14595 142 Diels-Alderase hypothetical protein, Frankia sp. EI5c (WP_066064649.1); 97/99 AbyU AbsU AbmU 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Frankia sp. EI5c CC117_RS14600 349 AbyA1 AbsA1 AbmA1 protein (WP_066064652.1); 94/96 CC117_RS14605 666 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Frankia sp. EI5c (WP_083986533.1); 88/90 AbyA2 AbsA2 AbmA2 TetR/AcrR family transcriptional CC117_RS14610 209 transcriptional regulator, Frankia sp. EI5c (OAA27545.1); 94/96 - - - regulator drug resistance transporter, EmrB/QacA subfamily, Frankia sp. EI5c CC117_RS14615 519 MFS transporter AbyD AbsD AbmD (OAA27546.1); 88/90 LLM class flavin-dependent luciferase family oxidoreductase, group 1, Frankia sp. EI5c (OAA27547.1); CC117_RS14620 336 AbyE AbsE AbmE1 oxidoreductase 93/96 helix-turn-helix transcriptional regulator, Frankia sp. EI5c (WP_066064661.1); CC117_RS14625 1031 LuxR family transcriptional regulator AbyH - AbmH 88/91 AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Frankia sp. EI5c CC117_RS14630 257 AbyI - AbmI regulator (WP_066064664.1); 89/94 CC117_RS14635 76 acyl carrier protein acyl carrier protein, Frankia sp. EI5c (WP_066064666.1); 97/97 AbyA3 AbsA3 AbmA3 CC117_RS14640 293 acyltransferase acyltransferase, Frankia sp. EI5c (WP_066064669.1); 86/88 AbyA4 AbsA4 AbmA4 CC117_RS14645 359 alpha/beta hydrolase alpha/beta hydrolase, Frankia sp. EI5c (WP_066064673.1); 94/95 AbyA5 AbsA5 AbmA5 CC117_RS36320 - PKS I type I polyketide synthase, partial, Frankia sp. EI5c (WP_066064676.1); 83/85 PKS I PKS I PKS I SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS34795 - PKS I PKS I PKS I PKS I (WP_128423201.1); 85/88 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS34800 - PKS I PKS I PKS I PKS I (WP_128423201.1); 73/77 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS34805 - PKS I PKS I PKS I PKS I (WP_128423201.1); 94/96 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS34810 - PKS I PKS I PKS I PKS I (WP_128423201.1); 64/68 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS34820 - PKS I PKS I PKS I PKS I (WP_128423201.1); 79/82 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS34825 - PKS I PKS I PKS I PKS I (WP_128423201.1); 77/81 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS36325 - PKS I PKS I PKS I PKS I (WP_128423201.1 ); 66/74 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS34840 - PKS I PKS I PKS I PKS I (WP_128423214.1); 75/78 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS34845 - PKS I PKS I PKS I PKS I (WP_128423214.1); 78/81 KR domain-containing protein, partial, Frankia sp. EI5c (WP_128423221.1); CC117_RS36330 - PKS I PKS I PKS I PKS I 87/88

62 SDR family NAD(P)-dependent oxidoreductase, partial, Frankia sp. EI5c CC117_RS14660 - PKS I PKS I PKS I PKS I (WP_066069977.1); 80/84 CC117_RS36335 - PKS I type I polyketide synthase, Frankia sp. EI5c (WP_066069974.1); 90/92 PKS I PKS I PKS I CC117_RS36340 - PKS I type I polyketide synthase, Frankia sp. EI5c (WP_066069974.1); 78/80 PKS I PKS I PKS I CC117_RS36345 - PKS I type I polyketide synthase, Frankia sp. EI5c (WP_066069974.1); 94/96 PKS I PKS I PKS I CC117_RS36350 - PKS I type I polyketide synthase, Frankia sp. EI5c (WP_066069974.1); 83/85 PKS I PKS I PKS I CC117_RS36355 - PKS I type I polyketide synthase, Frankia sp. EI5c (WP_066069974.1); 77/79 PKS I PKS I PKS I CC117_RS36360 - PKS I type I polyketide synthase, Frankia sp. EI5c (WP_066069974.1); 85/88 PKS I PKS I PKS I CC117_RS14670 - PKS I type I polyketide synthase, Frankia sp. EI5c (WP_066069971.1); 83/86 PKS I PKS I PKS I CC117_RS14675 501 hypothetical protein hypothetical protein, Frankia sp. EI5c (WP_066069968.1); 90/93 - - - CC117_RS14680 344 hypothetical protein hypothetical protein, Frankia sp. EI5c (WP_066069965.1); 93/96 - - - CC117_RS14685 255 ABC transporter permease ABC transporter permease, Frankia sp. EI5c (WP_066069963.1); 97/98 - - - ABC transporter ATP-binding protein, Frankia sp. EI5c (WP_066069960.1); CC117_RS14690 228 ABC transporter ATP-binding protein AbyF4 AbsF4 AbmF4 95/97 nuclear transport factor 2 family nuclear transport factor 2 family protein, Frankia sp. EI5c (WP_066069958.1); CC117_RS14695 212 - - - protein 87/87 CC117_RS14700 474 FAD-binding protein FAD-dependent oxidoreductase, Frankia sp. EI5c (WP_066069956.1); 93/95 - - - TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Streptomyces mirabilis CC117_RS14705 214 - - - regulator (WP_075032561.1); 98/99 SDR family oxidoreductase, Streptosporangium sp. 'caverna' CC117_RS14710 245 SDR family oxidoreductase - - - (WP_110706182.1); 99/99 CC117_RS14715 208 NADP oxidoreductase NADP oxidoreductase, Streptomyces mirabilis (WP_075032563.1); 98/99 - - - TIGR03619 family F420-dependent TIGR03619 family F420-dependent LLM class oxidoreductase, Streptomyces CC117_RS14720 301 - - - LLM class oxidoreductase violaceoruber (WP_030946214.1); 91/92 CC117_RS34855 277 hypothetical protein hypothetical protein, Frankia sp. EI5c (WP_066069953.1); 92/94 - - - TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Frankia sp. EI5c CC117_RS14730 206 - AbsC2 - regulator (WP_083986911.1); 79/82 CC117_RS14735 209 hypothetical protein hypothetical protein, Frankia elaeagni (WP_018637321.1); 94/97 - - -

63 Table S34. Predicted functions of ORFs surrounding AbyU homolog from Photobacterium ganghwense JCM 12487 (NZ_PYMI01000004.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog C9I92_RS15395 - IS481 family transposase ISSod13, transposase, Vibrio cholerae (SYZ80217.1); 85/91 - - - TetR family transcriptional TetR/AcrR family transcriptional regulator, Vibrio proteolyticus C9I92_RS15400 157 - - - regulator (WP_081693121.1); 87/94 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Oceanimonas baumannii C9I92_RS15405 439 - - - oxidoreductase (WP_094278553.1); 83/89 ABC transporter ATP-binding ABC transporter ATP-binding protein, Oceanimonas baumannii C9I92_RS15410 167 - - - protein (WP_094278554.1); 58/73 TonB-dependent siderophore TonB-dependent siderophore receptor, Oceanimonas baumannii C9I92_RS15415 683 - - - receptor (WP_094278589.1); 79/89 DHA2 family efflux MFS transporter permease subunit, Salinivibrio sp. YCSC6 C9I92_RS15420 518 MFS transporter - - - (WP_096632410.1); 89/93 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Vibrio gazogenes (WP_088133275.1); C9I92_RS15425 210 - - - regulator 88/92 ABC transporter ATP-binding ABC transporter ATP-binding protein, Janthinobacterium lividum C9I92_RS15430 263 - - - protein (WP_128140012.1); 61/77 iron-siderophore ABC transporter permease, Burkholderia sp. BDU5 C9I92_RS15435 376 iron ABC transporter permease - - - (KVE40442.1); 63/80 TonB-dependent siderophore receptor, Janthinobacterium lividum C9I92_RS15440 164 TonB-dependent receptor - - - (WP_128140009.1); 36/44 hypothetical protein BW21_4870, Burkholderia sp. 2002721687 (AJY38756.1); C9I92_RS15445 91 hypothetical protein - - - 61/71 siderophore biosynthesis protein, Xenorhabdus thuongxuanensis C9I92_RS15450 536 siderophore biosynthesis - - - (WP_074020647.1); 64/77 C9I92_RS15455 260 alpha/beta fold hydrolase thioesterase, Xenorhabdus thuongxuanensis (WP_074020648.1); 58/72 - - - pyridoxal-phosphate dependent pyridoxal-phosphate dependent enzyme family protein, Burkholderia sp. ABCPW C9I92_RS15460 348 - - - enzyme 111 (KGS01917.1); 74/84 C9I92_RS15465 191 Diels-Alderase hypothetical protein, Xenorhabdus beddingii (WP_086111861.1); 71/86 AbyU AbsU AbmU acyltransferase domain-containing acyltransferase domain-containing protein, Xenorhabdus beddingii C9I92_RS15470 965 - - - protein (WP_086111860.1); 63/77 C9I92_RS15475 335 leucine dehydrogenase leucine dehydrogenase, Xenorhabdus beddingii (WP_086111859.1); 68/82 - - - ABC transporter substrate-binding ABC transporter substrate-binding protein, Xenorhabdus beddingii C9I92_RS15480 380 - - - protein (WP_086111858.1); 67/78 FAD-dependent oxidoreductase, Xenorhabdus thuongxuanensis C9I92_RS15485 424 FAD-dependent oxidoreductase - - - (WP_074020653.1); 74/85 phosphonate ABC transporter, phosphonate ABC transporter, permease protein PhnE, Vibrio parahaemolyticus C9I92_RS15490 266 - - - permease protein PhnE (WP_069543805.1); 81/90 phosphonate ABC transporter phosphonate ABC transporter ATP-binding protein, Vibrio campbellii C9I92_RS15495 271 - - - ATP-binding protein (WP_122020405.1); 83/91 phosphonate ABC transporter phosphate/phosphite/phosphonate ABC transporter substrate-binding protein, C9I92_RS15500 283 - - - substrate-binding protein Vibrio maritimus (WP_081941364.1); 81/89

64 iron-containing alcohol dehydrogenase, Vibrio maritimus (WP_042495142.1); C9I92_RS15505 363 phosphonoacetaldehyde reductase - - - 62/76 LysR family transcriptional C9I92_RS15510 299 LysR family transcriptional regulator, Vibrio campbellii (WP_045456615.1); 65/84 - - - regulator C9I92_RS15515 295 DMT family transporter DMT family transporter, Photobacterium marinum (WP_007465237.1); 71/82 - - - C9I92_RS15520 675 elongation factor G elongation factor G, Photobacterium sanctipauli (WP_036815829.1); 78/89 - - -

65 Table S35. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces geranii A301 (NZ_PJME01000012.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog CW359_RS1838 1119 peptidase 1,4-dihydropyridine esterase, Streptomyces sp. L-9-10 (WP_129768931.1); 52/65 - - - 0 CW359_RS1838 69 hypothetical protein hypothetical protein, Streptomyces sp. NL15-2K (WP_124445691.1); 93/98 - - - 5 CW359_RS1839 75 hypothetical protein hypothetical protein, Streptomyces sp. NL15-2K (WP_124445690.1); 80/87 - - - 0 CW359_RS1839 145 Diels-Alderase hypothetical protein, Streptomyces sp. NL15-2K (WP_124445689.1); 92/97 AbyU AbsU AbmU 5 CW359_RS1840 354 hypothetical protein hypothetical protein, Streptomyces sp. NL15-2K (WP_124445688.1); 92/95 - - - 0 CW359_RS1840 355 alpha/beta hydrolase alpha/beta fold hydrolase, Streptomyces sp. NL15-2K (WP_124445687.1); 76/80 - - - 5 CW359_RS1841 197 hypothetical protein acyltransferase, Streptomyces sp. NL15-2K (WP_124445686.1); 79/86 - - - 0 CW359_RS1841 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. NL15-2K 1543 PKS I - - - 5 (WP_124445724.1); 82/87 CW359_RS1842 287 thioesterase thioesterase, Streptomyces sp. NL15-2K (WP_124445723.1); 79/84 - - - 0 CW359_RS1842 DHA2 family efflux MFS transporter permease subunit, Streptomyces sp. NL15-2K 481 multidrug efflux MFS transporter - - - 5 (WP_124445722.1); 87/92 CW359_RS1843 amino acid adenylation domain-containing protein, Streptomyces sp. NL15-2K 1029 non-ribosomal peptide synthetase - - - 0 (WP_124445721.1); 83/87 CW359_RS1843 273 hypothetical protein hypothetical protein, Streptomyces sp. NL15-2K (WP_124445720.1); 81/86 - - - 5 CW359_RS1844 248 thioesterase alpha/beta fold hydrolase, Streptomyces sp. NL15-2K (WP_124445719.1); 82/89 - - - 0 CW359_RS1844 pyridoxal-phosphate dependent pyridoxal-phosphate dependent enzyme, Streptomyces sp. NL15-2K 347 - - - 5 enzyme (WP_124445718.1); 83/87 CW359_RS1845 helix-turn-helix domain containing 312 IS630 family transposase, Streptomyces sp. NL15-2K (WP_124445717.1); 59/67 - - - 0 protein CW359_RS1845 AfsR/SARP family transcriptional 257 regulatory protein, Streptomyces sp. NL15-2K (GCB53297.1); 80/90 - - - 5 regulator CW359_RS1846 helix-turn-helix transcriptional helix-turn-helix transcriptional regulator, Streptomyces sp. NL15-2K 935 - - - 0 regulator (WP_124445716.1); 70/79 CW359_RS1846 105 hypothetical protein hypothetical protein, Streptomyces sp. NL15-2K (WP_124445715.1); 69/82 - - - 5 CW359_RS1847 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Streptomyces sp. NL15-2K 196 - - - 0 regulator (WP_124445714.1); 88/94

66 Table S36. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces griseocarneus 132 (NZ_PENC01000003).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog SDR family NAD(P)-dependent oxidoreductase, Streptomyces orinoci CTZ27_RS09805 1351 PKS I - - - (WP_109280288.1); 46/56 CTZ27_RS09810 2970 PKS I type I polyketide synthase, Saccharothrix sp. CB00851 (WP_073887745.1); 53/63 - - - CTZ27_RS09815 413 cytochrome P450 cytochrome P450, Streptomyces sp. NRRL F-6491 (KOX15956.1); 60/72 - - - nuclear transport factor 2 nuclear transport factor 2 family protein, Micromonosporaceae bacterium CPCC CTZ27_RS09820 149 - - - family protein 204380 (WP_117208645.1); 45/60 CTZ27_RS09825 133 Diels-Alderase hypothetical protein, Streptomyces sp. MUSC 14 (WP_071375955.1); 40/55 AbyU AbsU AbmU crotonyl-CoA CTZ27_RS09830 418 crotonyl-CoA carboxylase/reductase, Saccharothrix texasensis (ROP35577.1); 72/82 - - - carboxylase/reductase LuxR family transcriptional hypothetical protein ADL06_14810, Streptomyces sp. NRRL F-6491 (KOX27187.1); CTZ27_RS09835 306 - - - regulator 45/59 MarR family transcriptional CTZ27_RS09840 178 MarR family transcriptional regulator, Streptomyces orinoci (WP_109280519.1); 82/88 - - - regulator CTZ27_RS09845 103 hypothetical protein hypothetical protein, Streptomyces canus (WP_059204811.1); 58/64 - - - CTZ27_RS09850 412 sensor histidine kinase sensor histidine kinase, Streptacidiphilus rugosus (WP_037608268.1); 76/81 - - - response regulator CTZ27_RS09855 216 response regulator, Streptomyces sp. BK308 (WP_132857399.1); 88/93 - - - transcription factor CTZ27_RS09860 - uroporphyrinogen-III synthase uroporphyrinogen-III synthase, Kitasatospora mediocidica (WP_051966293.1); 80/87 - - - CTZ27_RS09865 712 nitrite reductase nitrite reductase, Streptomyces cattleya (WP_014151313.1); 84/87 - - - NAD(P)/FAD-dependent CTZ27_RS09870 405 nitrite reductase, Streptomyces malaysiense (OIK25113.1); 71/76 - - - oxidoreductase CTZ27_RS09875 855 nitrite reductase large subunit nitrite reductase large subunit, Streptomyces cattleya (WP_014151311.1); 83/89 - - - nitrite reductase small subunit nitrite reductase (NADH) small subunit, Streptomyces misionensis (SED96007.1); CTZ27_RS09880 145 - - - NirD 71/84 NarK/NasA family nitrate nitrite reductase small subunit NirD, Streptomyces sp. MBT76 (WP_079110603.1); CTZ27_RS09885 458 - - - transporter 75/84 GNAT family N- CTZ27_RS09890 176 GNAT family N-acetyltransferase, Streptomyces olivoreticuli (WP_116209751.1); 85/92 - - - acetyltransferase

67 Table S37. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces griseorubiginosus SAI-142 (NZ_RJKZ01000001.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog LuxR family transcriptional LuxR family transcriptional regulator, Streptomyces regalis (WP_062712128.1); EDC83_RS30485 912 AbyH - AbmH regulator 38/51 AfsR/SARP family transcriptional EDC83_RS30490 257 activator protein, Streptomyces sp. BK438 (WP_132903690.1); 70/79 AbyI - AbmI regulator EDC83_RS30495 278 thioesterase thioesterase, Streptomyces hoynatensis (WP_120684679.1); 48/58 AbyT AbsN AbmT 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Streptomyces paucisporeus EDC83_RS30500 343 AbyA1 AbsA1 AbmA1 protein (WP_073498468.1); 64/77 EDC83_RS30505 257 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Streptomyces armeniacus (AXK32418.1); 59/71 AbyA2 AbsA2 AbmA2 EDC83_RS30510 75 acyl carrier protein acyl carrier protein, Actinomadura sp. 7K507 (WP_132147234.1); 57/82 AbyA3 AbsA3 AbmA3 EDC83_RS30515 268 acyltransferase acyltransferase, Streptomyces kanamyceticus (WP_055549000.1); 60/77 AbyA4 AbsA4 AbmA4 EDC83_RS30520 372 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces sp. NRRL F-525 (WP_033287161.1); 52/64 AbyA5 AbsA5 AbmA5 EDC83_RS30525 248 hypothetical protein S-adenosyl methyltransferase, Actinomadura umbrina (REE95466.1); 51/69 - - - EDC83_RS30530 6378 PKS I type I polyketide synthase, Actinomadura macra (WP_067456430.1); 55/66 AbyB1 AbsB1 AbmB1 EDC83_RS30535 2213 PKS I type I polyketide synthase, Streptomyces formicae (WP_098241246.1); 56/67 AbyB2 AbsB2 AbmB2 EDC83_RS30540 1554 PKS I Erythronolide synthase, Streptomyces malaysiensis (PNG90733.1); 49/61 AbyB3 AbsB3 AbmB3 2-polyprenyl-6-methoxyphenol hydroxylase, Kibdelosporangium aridum EDC83_RS30545 581 hypothetical protein - - - (WP_037262367.1); 47/59 EDC83_RS30550 61 hypothetical protein hypothetical protein, Streptomyces sp. 57 (WP_121408886.1); 56/60 - - - EDC83_RS30555 348 methyltransferase methyltransferase, Nonomuraea wenchangensis (WP_091076886.1); 48/59 - - - EDC83_RS30560 137 Diels-Alderase hypothetical protein, Streptomyces paucisporeus (WP_073498104.1); 44/58 AbyU AbsU AbmU EDC83_RS30565 78 ferredoxin ferredoxin, Streptomyces sp. GSSD-12 (WP_114664483.1); 59/70 - AbsG1 AbmG EDC83_RS30570 369 cytochrome P450 cytochrome P450, Streptomyces paucisporeus (WP_073498464.1); 56/71 AbyX/AbyV AbsV/AbsX AbmV DHA2 family efflux MFS transporter permease subunit, Streptomyces formicae EDC83_RS30575 501 MFS transporter AbyD AbsD AbmD (WP_098241238.1); 52/68 TetR/AcrR family transcriptional TetR family transcriptional regulator, Nonomuraea sp. CH32 (WP_132623500.1); EDC83_RS30580 174 AbyC - AbmC regulator 53/67 nucleotidyl transferase nucleotidyl transferase AbiEii/AbiGii toxin family protein, Streptomyces sp. NRRL EDC83_RS30585 45 - - - AbiEii/AbiGii toxin family protein F-525 (WP_033282780.1); 82/86 EDC83_RS30590 174 hypothetical protein - - - - L-serine ammonia-lyase, Streptomyces sp. 351MFTsu5.1 (WP_020139905.1); EDC83_RS30595 455 L-serine ammonia-lyase - - - 98/99 serine hydroxymethyltransferase, Streptomyces sp. NRRL B-24085 EDC83_RS30600 421 serine hydroxymethyltransferase - - - (WP_053846967.1); 98/98

68 glycine cleavage system protein glycine cleavage system H protein, Streptomyces sviceus ATCC 29083 EDC83_RS30605 125 - - - GcvH (EDY54000.1); 100/100 glycine cleavage system glycine cleavage system aminomethyltransferase GcvT, Streptomyces sp. NRRL EDC83_RS30610 371 - - - aminomethyltransferase GcvT B-24085 (WP_053846965.1); 95/97 EDC83_RS30615 222 ATP-binding protein AAA domain-containing protein, Streptomyces sp. BK205 (TCR18702.1); 95/96 - - - enhanced serine sensitivity enhanced serine sensitivity protein SseB, Streptomyces sp. BK205 EDC83_RS30620 263 - - - protein SseB (WP_132837573.1); 99/100 enhanced serine sensitivity type III secretion system (T3SS) SseB-like protein, Streptomyces sp. BK205 EDC83_RS30625 264 - - - protein SseB (TCR18704.1); 97/98 ABC transporter permease, Streptomyces sp. W SAI-097 (WP_123991755.1); EDC83_RS30630 332 ABC transporter permease AbyF3 AbsF3 AbmF3 99/99 ABC transporter substrate- ABC transporter substrate-binding protein, Streptomyces mirabilis EDC83_RS30635 582 - - - binding protein (WP_037711494.1); 98/98 ABC transporter permease, Streptomyces sp. W SAI-097 (WP_123991757.1); EDC83_RS30640 335 ABC transporter permease AbyF2 AbsF2 AbmF2 99/100 ABC transporter ATP-binding ABC transporter ATP-binding protein, Streptomyces sp. NRRL B-24085 EDC83_RS30645 363 AbyF4 AbsF4 AbmF4 protein (WP_053846961.1); 99/99 dipeptide ABC transporter ATP- dipeptide ABC transporter ATP-binding protein, Streptomyces sp. NRRL B-3229 EDC83_RS30650 446 AbyF4 AbsF4 AbmF4 binding protein (WP_037819546.1); 86/88

69 Table S38. Predicted functions of ORFs in abyssomicin BGC from Herbidospora daliensis NBRC 106372 (NZ_BBXF01000001.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) LLM class F420-dependent LLM class F420-dependent oxidoreductase, Herbidospora cretacea AW274_RS02325 285 - - AbmE2 oxidoreductase (WP_030454059.1); 93/95 AfsR/SARP family AW274_RS02330 257 activator protein, Herbidospora sakaeratensis (WP_062343034.1); 96/98 AbyI - AbmI transcriptional regulator AW274_RS02335 248 thioesterase thioesterase, Herbidospora sakaeratensis (WP_062343032.1); 90/92 AbyT AbsN AbmT LuxR family transcriptional helix-turn-helix transcriptional regulator, Herbidospora sakaeratensis AW274_RS02340 897 AbyH - AbmH regulator (WP_062343030.1); 92/93 RHS repeat protein, Herbidospora sakaeratensis (WP_062343029.1); AW274_RS02345 836 RHS repeat protein AbyK - - 91/94 hypothetical protein, Herbidospora sakaeratensis (WP_062343027.1); AW274_RS02350 134 Diels-Alderase AbyU AbsU AbmU 99/100 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Herbidospora sakaeratensis AW274_RS02355 340 AbyA1 AbsA1 AbmA1 family protein (WP_062343025.1); 98/98 HAD-IIIC family phosphatase, Herbidospora sakaeratensis AW274_RS02360 614 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 (WP_062343023.1); 94/96 AW274_RS02370 322 acyltransferase acyltransferase, Herbidospora sakaeratensis (WP_062343019.1); 93/95 AbyA4 AbsA4 AbmA4 alpha/beta hydrolase, Herbidospora sakaeratensis (WP_062343017.1); AW274_RS02375 347 alpha/beta hydrolase AbyA5 AbsA5 AbmA5 95/97 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Herbidospora yilanensis AW274_RS02380 213 AbyC - AbmC regulator (WP_062349591.1); 98/99 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Herbidospora AW274_RS02385 476 AbyD AbsD AbmD transporter permease subunit sakaeratensis (WP_062343013.1); 97/98 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Herbidospora AW274_RS02390 335 AbyE AbsE AbmE1 oxidoreductase sakaeratensis (WP_062343011.1); 96/98 ABC transporter substrate- ABC transporter substrate-binding protein, Herbidospora sakaeratensis AW274_RS02395 543 AbyF1 AbsF1 AbmF1 binding protein (WP_062343009.1); 97/98 ABC transporter permease, Herbidospora sakaeratensis AW274_RS02400 317 ABC transporter permease AbyF2 AbsF2 AbmF2 (WP_083977791.1); 98/99 ABC transporter permease, Herbidospora cretacea (WP_034385023.1); AW274_RS02405 268 ABC transporter permease AbyF3 AbsF3 AbmF3 95/98 ABC transporter ATP-binding ABC transporter ATP-binding protein, Herbidospora sakaeratensis AW274_RS02410 529 AbyF4 AbsF4 AbmF4 protein (WP_062343005.1); 95/96 AW274_RS02415 376 acyltransferase acyltransferase, Herbidospora sakaeratensis (WP_062343003.1); 93/94 - AbsI - cytochrome P450, Herbidospora sakaeratensis (WP_062343001.1); AW274_RS02420 393 cytochrome P450 AbyV/AbyX AbsV/AbsX AbmV 97/98 AW274_RS02425 63 ferredoxin ferredoxin, Herbidospora sakaeratensis (WP_062343000.1); 97/98 - AbsG2/AbsG1 AbmG alpha/beta hydrolase, Herbidospora yilanensis (WP_062349582.1); AW274_RS02430 286 alpha/beta hydrolase - - - 91/95 AW274_RS38765 - PKS I type I polyketide synthase, Herbidospora mongoliensis AbyB1 AbsB1 AbmB1 (WP_066363856.1); 94/95

70 type I polyketide synthase, Herbidospora mongoliensis AW274_RS38770 PKS I (WP_066363856.1); 78/79 type I polyketide synthase, Herbidospora mongoliensis AW274_RS38775 PKS I (WP_066363856.1); 86/89 type I polyketide synthase, Herbidospora mongoliensis AW274_RS38780 PKS I (WP_066363856.1); 86/90 type I polyketide synthase, Herbidospora mongoliensis AW274_RS38785 PKS I (WP_066363856.1); 73/82 AW274_RS38790 PKS I - type I polyketide synthase, Herbidospora mongoliensis AW274_RS38795 PKS I (WP_066363856.1); 75/82 type I polyketide synthase, Herbidospora mongoliensis AW274_RS38800 PKS I (WP_066363856.1); 85/90 type I polyketide synthase, Herbidospora mongoliensis AW274_RS38805 PKS I (WP_066363856.1); 82/87 type I polyketide synthase, Herbidospora mongoliensis AW274_RS38810 PKS I (WP_066363856.1); 78/86 type I polyketide synthase, Herbidospora mongoliensis AW274_RS38815 PKS I (WP_066363856.1); 74/81 type I polyketide synthase, Herbidospora sakaeratensis AW274_RS38820 PKS I (WP_062342995.1); 88/90 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. AW274_RS02440 3774 PKS I AbyB2 AbsB2 AbmB2 BK438 (WP_132903672.1); 63/71 type I polyketide synthase, Herbidospora sakaeratensis AW274_RS02445 1019 PKS I AbyB3 AbsB3 AbmB3 (WP_062333186.1); 90/91 cytochrome P450, Herbidospora sakaeratensis (WP_062333189.1); AW274_RS02450 386 cytochrome P450 AbyX/AbyV AbsV/AbsX AbmV 94/97

71 Table S39. Predicted functions of ORFs in abyssomicin BGC from Herbidospora mongoliensis NBRC 105882 (NZ_BBXD01000011.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) ABC transporter ATP- ABC transporter ATP-binding protein, Herbidospora yilanensis AW272_RS12035 501 AbyF4 AbsF4 AbmF4 binding protein (WP_062349605.1); 79/84 ABC transporter permease, Herbidospora yilanensis (WP_063910013.1); AW272_RS12040 278 ABC transporter permease AbyF3 AbsF3 AbmF3 94/95 ABC transporter permease, Herbidospora yilanensis (WP_062349604.1); AW272_RS12045 318 ABC transporter permease AbyF2 AbsF2 AbmF2 94/96 ABC transporter substrate-binding protein, Herbidospora yilanensis AW272_RS12050 530 hypothetical protein AbyF1 AbsF1 AbmF1 (WP_062349603.1); 89/92 AfsR/SARP family AW272_RS12055 252 activator protein, Herbidospora yilanensis (WP_062349599.1); 88/91 AbyI - AbmI transcriptional regulator AW272_RS12060 249 thioesterase thioesterase, Herbidospora yilanensis (WP_083949863.1); 88/89 AbyT AbsN AbmT AW272_RS40525 1708 hypothetical protein RHS repeat protein, Herbidospora yilanensis (WP_062349597.1); 86/90 AbyK - - AW272_RS12075 134 Diels-Alderase hypothetical protein, Herbidospora (WP_030454064.1); 97/99 AbyU AbsU AbmU 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Herbidospora daliensis AW272_RS12080 340 AbyA1 AbsA1 AbmA1 family protein (WP_062428856.1); 94/96 HAD-IIIC family HAD-IIIC family phosphatase, Herbidospora sakaeratensis AW272_RS12085 630 AbyA2 AbsA2 AbmA2 phosphatase (WP_062343023.1); 89/91 AW272_RS12090 75 acyl carrier protein hypothetical protein, Herbidospora yilanensis (WP_062349594.1); 92/97 AbyA3 AbsA3 AbmA3 AW272_RS12095 247 acyltransferase Acyltransferase, Herbidospora yilanensis (WP_062349593.1); 94/96 AbyA4 AbsA4 AbmA4 AW272_RS12100 347 alpha/beta hydrolase alpha/beta hydrolase, Herbidospora yilanensis (WP_062349592.1); 92/95 AbyA5 AbsA5 AbmA5 TetR/AcrR family TetR/AcrR family transcriptional regulator, Herbidospora sakaeratensis AW272_RS12105 217 AbyC - AbmC transcriptional regulator (WP_062343015.1); 94/96 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Herbidospora AW272_RS12110 475 transporter permease AbyD AbsD AbmD yilanensis (WP_062349590.1); 92/95 subunit LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Herbidospora sakaeratensis AW272_RS12115 335 AbyE AbsE AbmE1 oxidoreductase (WP_062343011.1); 92/95 ABC transporter substrate- ABC transporter substrate-binding protein, Herbidospora daliensis AW272_RS12120 544 AbyF1 AbsF1 AbmF1 binding protein (WP_062428872.1); 90/94 ABC transporter permease, Herbidospora yilanensis (WP_062349773.1); AW272_RS12125 317 ABC transporter permease AbyF2 AbsF2 AbmF2 93/96 ABC transporter permease, Herbidospora cretacea (WP_034385023.1); AW272_RS12130 268 ABC transporter permease AbyF3 AbsF3 AbmF3 92/95 ABC transporter ATP- ABC transporter ATP-binding protein, Herbidospora cretacea AW272_RS12135 529 AbyF4 AbsF4 AbmF4 binding protein (WP_030454076.1); 90/94 AW272_RS12140 388 acyltransferase Acyltransferase, Herbidospora sakaeratensis (WP_062343003.1); 90/93 - AbsI - AW272_RS12145 393 cytochrome P450 cytochrome P450, Herbidospora sakaeratensis (WP_062343001.1); 95/97 AbyV/AbyX AbsV/AbsX AbmV AW272_RS12150 63 ferredoxin Ferredoxin, Herbidospora sakaeratensis (WP_062343000.1); 95/98 - AbsG2/AbsG1 AbmG

72 AW272_RS12155 288 alpha/beta hydrolase alpha/beta hydrolase, Herbidospora yilanensis (WP_062349582.1); 91/93 - - - AW272_RS12160 6103 PKS I type I polyketide synthase, Streptomyces fragilis (WP_108952947.1); 59/67 AbyB1 AbsB1 AbmB1 type I polyketide synthase, Herbidospora daliensis (WP_062428883.1); AW272_RS12165 3854 PKS I AbyB2 AbsB2 AbmB2 80/84 type I polyketide synthase, Herbidospora daliensis (WP_062428886.1); AW272_RS12170 1070 PKS I AbyB3 AbsB3 AbmB3 81/86 AW272_RS12175 386 cytochrome P450 cytochrome P450, Herbidospora sakaeratensis (WP_062333189.1); 91/95 AbyX/AbyV AbsV/AbsX AbmV

73 Table S40. Predicted functions of ORFs in abyssomicin BGC from Herbidospora sakaeratensis NBRC 102641 (NZ_BBXC01000032).

Size Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog (aa) homolog type I polyketide synthase, Herbidospora daliensis (WP_062428883.1); AW271_RS37390 - PKS I PKS I PKS I PKS I 89/91 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. 57 AW271_RS37395 5982 PKS I AbyB1 AbsB1 AbmB1 (WP_121408907.1); 57/65 AW271_RS37400 286 alpha/beta hydrolase alpha/beta hydrolase, Herbidospora yilanensis (WP_062349582.1);94/96 - - - AW271_RS37405 63 ferredoxin ferredoxin, Herbidospora yilanensis (WP_062349583.1); 98/100 - AbsG2/AbsG1 AbmG AW271_RS37410 393 cytochrome P450 cytochrome P450, Herbidospora daliensis (WP_062428876.1); 97/98 AbyV/AbyX AbsV/AbsX AbmV AW271_RS37415 380 acyltransferase acyltransferase, Herbidospora mongoliensis (WP_066363851.1); 90/93 - AbsI - ABC transporter ATP-binding ABC transporter ATP-binding protein, Herbidospora daliensis AW271_RS37420 534 AbyF4 AbsF4 AbmF4 protein (WP_062428874.1); 96/98 ABC transporter permease, Herbidospora cretacea (WP_034385023.1); AW271_RS37425 268 ABC transporter permease AbyF3 AbsF3 AbmF3 96/98 ABC transporter permeasem, Herbidospora daliensis AW271_RS37430 317 ABC transporter permease AbyF2 AbsF2 AbmF2 (WP_062430092.1); 98/99 ABC transporter substrate- ABC transporter substrate-binding protein, Herbidospora daliensis AW271_RS37435 543 AbyF1 AbsF1 AbmF1 binding protein (WP_062428872.1); 97/98 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Herbidospora cretacea AW271_RS37440 335 AbyE AbsE AbmE1 oxidoreductase (WP_030454072.1); 98/98 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Herbidospora AW271_RS37445 476 AbyD AbsD AbmD transporter permease subunit daliensis (WP_062428868.1); 97/98 TetR/AcrR family TetR/AcrR family transcriptional regulator, Herbidospora yilanensis AW271_RS37450 217 AbyC - AbmC transcriptional regulator (WP_062349591.1); 98/99 AW271_RS37455 347 alpha/beta hydrolase alpha/beta hydrolase, Herbidospora daliensis (WP_062428864.1); 95/97 AbyA5 AbsA5 AbmA5 AW271_RS37460 244 acyltransferase acyltransferase, Herbidospora yilanensis (WP_062349593.1); 95/96 AbyA4 AbsA4 AbmA4 acyl carrier protein, Herbidospora mongoliensis (WP_066363836.1); AW271_RS37465 75 hypothetical protein AbyA3 AbsA3 AbmA3 92/97 HAD-IIIC family phosphatase, Herbidospora yilanensis AW271_RS37470 630 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 (WP_062349595.1); 93/96 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Herbidospora daliensis AW271_RS37475 340 AbyA1 AbsA1 AbmA1 family protein (WP_062428856.1); 98/98 AW271_RS37480 134 Diels-Alderase hypothetical protein, Herbidospora daliensis (WP_062428853.1); 99/100 AbyU AbsU AbmU AW271_RS37485 836 RHS repeat protein RHS repeat protein, Herbidospora daliensis (WP_062428851.1); 91/94 AbyK - - helix-turn-helix transcriptional LuxR family transcriptional regulator, Herbidospora daliensis AW271_RS37490 898 AbyH - AbmH regulator (WP_062428849.1); 92/93 AW271_RS37495 251 thioesterase thioesterase, Herbidospora yilanensis (WP_083949863.1); 91/92 AbyT AbsN AbmT AfsR/SARP family AW271_RS37500 257 activator protein, Herbidospora yilanensis (WP_062349599.1); 98/98 AbyI - AbmI transcriptional regulator

74 LLM class F420-dependent LLM class F420-dependent oxidoreductase, Herbidospora cretacea AW271_RS37505 285 - - AbmE2 oxidoreductase (WP_030454059.1); 93/95

75 Table S41. Predicted functions of ORFs in potential abyssomicin BGC from Actinokineospora inagensis DSM 44258 (NZ_AXWW01000024.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) AfsR/SARP family H504_RS0110020 257 activator protein, Amycolatopsis sp. CA-126428 (WP_103341808.1); 76/86 AbyI - AbmI transcriptional regulator H504_RS0110025 409 cytochrome P450 cytochrome P450, Amycolatopsis sp. CA-126428 (WP_103341807.1); 83/87 AbyX/AbyV AbsV/AbsX AbmV H504_RS0110030 64 ferredoxin ferredoxin-1, Amycolatopsis sp. CA-126428 (WP_103341806.1); 66/76 - AbsG1/AbsG2 AbmG multidrug efflux MFS DHA2 family efflux MFS transporter permease subunit, Amycolatopsis sp. H504_RS34265 498 AbyD AbsD AbmD transporter CA-126428 (WP_103341805.1); 70/79 nuclear transport factor nuclear transport factor 2 family protein, Amycolatopsis sp. CA-126428 H504_RS34270 155 - - - 2 family protein (WP_103341804.1); 69/81 helix-turn-helix H504_RS34275 267 transcriptional regulator, TetR family, Frankia sp. CcI6 (ETA00366.1); 56/70 - AbsC2 - transcriptional regulator H504_RS0110050 412 cytochrome P450 cytochrome P450, Amycolatopsis sp. CA-126428 (WP_103341801.1); 65/80 AbyX/AbyV AbsV/AbsX AbmV type I polyketide synthase, Streptomyces sp. JV178 (WP_099966065.1); H504_RS0110055 3768 PKS I PKS I PKS I PKS I 54/64 H504_RS0110060 6097 PKS I type I polyketide synthase, Actinomadura macra (WP_067456430.1); 53/64 PKS I PKS I PKS I hypothetical protein, Amycolatopsis sp. CA-126428 (WP_103337400.1); H504_RS0110065 167 Diels-Alderase AbyU AbsU AbmU 68/78 DHA2 family efflux MFS transporter permease subunit, Amycolatopsis sp. H504_RS34280 663 MFS transporter AbyD AbsD AbmD CA-126428 (WP_103337401.1); 86/92 type I polyketide synthase, Amycolatopsis sp. CA-126428 H504_RS0110075 1381 PKS I PKS I PKS I PKS I (WP_103337398.1); 65/74 SDR family NAD(P)-dependent oxidoreductase, Streptomyces olivoreticuli H504_RS34285 3465 PKS I PKS I PKS I PKS I (WP_116210514.1); 54/66 3-oxoacyl-ACP synthase 3-oxoacyl-ACP synthase III family protein, Amycolatopsis sp. CA-126428 H504_RS0110090 344 AbyA1 AbsA1 AbmA1 III family protein (WP_103342534.1); 82/90 HAD-IIIC family HAD-IIIC family phosphatase, Amycolatopsis sp. CA-126428 H504_RS34290 634 AbyA2 AbsA2 AbmA2 phosphatase (WP_103342533.1); 75/83 H504_RS0110100 74 hypothetical protein acyl carrier protein, Amycolatopsis sp. CA-126428 (WP_103342532.1); 64/79 AbyA3 AbsA3 AbmA3 H504_RS34295 259 acyltransferase acyltransferase, Amycolatopsis sp. CA-126428 (WP_103342540.1); 81/88 AbyA4 AbsA4 AbmA4 alpha/beta hydrolase, Amycolatopsis sp. CA-126428 (WP_103342531.1); H504_RS34300 372 alpha/beta hydrolase AbyA5 AbsA5 AbmA5 68/76

76 Table S42. Predicted functions of ORFs in potential BGC from Streptomyces iranensis DSM 41954 (NZ_LK022848).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Streptomyces sp. 11-1-2 SIRAN_RS44090 227 - - - regulator (WP_119984664.1); 89/91 NAD(P)-dependent alcohol NAD(P)-dependent alcohol dehydrogenase, Streptomyces rhizosphaericus SIRAN_RS44095 319 - - - dehydrogenase (WP_086879937.1); 94/96 SIRAN_RS44100 770 helicase helicase, Streptomyces rhizosphaericus (WP_086879936.1); 97/98 - - - SIRAN_RS44105 505 glycoside hydrolase glycoside hydrolase, Streptomyces rapamycinicus (WP_020874169.1); 97/98 - - - SIRAN_RS44110 144 hypothetical protein SRPBCC family protein, Streptomyces hygroscopicus (WP_030824776.1); 92/96 - - - SIRAN_RS44115 649 beta-N-acetylglucosaminidase hyaluronidase, Streptomyces rapamycinicus (WP_020874171.1); 95/96 - - - FAD-binding monooxygenase, Streptomyces sp. WAC05858 (WP_125755201.1); SIRAN_RS44120 440 FAD-dependent oxidoreductase - - - 90/94 glucan biosynthesis protein, Streptomyces rhizosphaericus (WP_086879933.1); SIRAN_RS44125 894 glucan biosynthesis protein - - - 97/97 nuclear transport factor 2 family nuclear transport factor 2 family protein, Saccharothrix syringae (WP_051765870.1); SIRAN_RS51845 154 - - - protein 87/92 NAD(P)-dependent NAD(P)-dependent oxidoreductase, Saccharothrix syringae (WP_051765824.1); SIRAN_RS51850 277 - - - oxidoreductase 87/93 SIRAN_RS51855 140 Diels-Alderase hypothetical protein, Streptomyces cattleya (WP_014140910.1); 91/95 AbyU AbsU AbmU nuclear transport factor 2 family nuclear transport factor 2 family protein, Streptomyces cattleya (WP_014627233.1); SIRAN_RS44130 119 - - - protein 93/97 SIRAN_RS44135 417 cytochrome P450 cytochrome P450, Saccharothrix syringae (WP_033431229.1); 93/97 - - - SIRAN_RS44140 6154 PKS I type I polyketide synthase, Streptomyces cattleya (WP_014140913.1); 89/93 - - - SIRAN_RS44145 159 PKS I type I polyketide synthase, Saccharothrix syringae (WP_084716421.1); 89/90 - - - SIRAN_RS51860 - PKS I type I polyketide synthase, Saccharothrix syringae (WP_084716421.1); 89/92 - - - pyridoxamine 5'-phosphate SIRAN_RS44165 - hypothetical protein, Saccharothrix syringae (WP_033431232.1); 88/94 - - - oxidase family protein SIRAN_RS44170 - PKS I type I polyketide synthase, Streptomyces cattleya (WP_014140917.1); 92/95 - - - acyltransferase domain-containing protein, Streptomyces cattleya SIRAN_RS44175 - PKS I - - - (WP_014140918.1); 91/93 transcriptional regulator, partial, Streptomyces milbemycinicus (WP_086861070.1); SIRAN_RS51865 - hypothetical protein - - - 60/67 SIRAN_RS44180 277 SDR family oxidoreductase SDR family oxidoreductase, Streptomyces cattleya (WP_014140897.1); 94/97 - - - LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces cattleya SIRAN_RS44185 393 - - - oxidoreductase (WP_014140896.1); 95/97 SIRAN_RS44190 68 thioesterase thioesterase, Streptomyces cattleya (WP_014140907.1); 96/98 - - -

77 SIRAN_RS44195 408 cytochrome P450 cytochrome P450, Streptomyces cattleya (WP_014627229.1); 88/93 - - - RNA-directed DNA polymerase, Streptomyces sp. SYSU K10008 SIRAN_RS51870 125 hypothetical protein - - - (WP_128381944.1); 87/89 helix-turn-helix transcriptional LuxR family transcriptional regulator, Saccharothrix syringae (WP_051765876.1); SIRAN_RS44205 933 - - - regulator 88/91 SIRAN_RS53370 83 hypothetical protein hypothetical protein, Streptomyces hygroscopicus (WP_078640395.1); 71/81 - - -

78 Table S43. Predicted functions of ORFs in potential abyssomicin BGC from Lentzea kentuckyensis NRRL B-24416 (NZ_MUYM01000068 and NZ_MUYM01000065).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog DUF418 domain-containing DUF1624 domain-containing protein, Lechevalieria aerocolonigenes B0F77_RS29650 306 - - - protein (WP_035909001.1); 78/88 B0F77_RS29655 171 hypothetical protein hypothetical protein, Lentzea terrae (WP_112264025.1); 89/92 - - - helix-turn-helix domain- XRE family transcriptional regulator, Streptomyces iranensis (WP_044572014.1); B0F77_RS29660 303 - - - containing protein 90/93 B0F77_RS29665 267 SDR family oxidoreductase 3-oxoacyl-ACP reductase, Streptomyces violaceusniger (KUL62983.1); 94/97 - - - ABC transporter ATP-binding ABC transporter ATP-binding protein, Lechevalieria deserti (WP_109636588.1); B0F77_RS29670 599 - - - protein 94/96 B0F77_RS29675 462 hypothetical protein hypothetical protein, Lentzea waywayandensis (WP_093606216.1); 92/94 - - - B0F77_RS29680 254 alpha/beta hydrolase alpha/beta fold hydrolase, Lentzea waywayandensis (WP_093592315.1); 79/91 - - - enoyl-CoA enoyl-CoA hydratase/isomerase family protein, Nocardia aobensis B0F77_RS29685 244 hydratase/isomerase family - - - (WP_051025421.1); 57/74 protein B0F77_RS29690 167 flavin reductase family protein flavin reductase, Actinomadura sp. WAC 06369 (WP_125618547.1); 66/73 AbyZ AbsH1 AbmZ 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. NRRL F-525 B0F77_RS29695 343 AbyA1 AbsA1 AbmA1 family protein (WP_033287157.1); 66/81 B0F77_RS29700 606 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Kutzneria buriramensis (WP_116181645.1); 58/71 AbyA2 AbsA2 AbmA2 B0F77_RS29705 75 acyl carrier protein acyl carrier protein, Frankia sp. ACN1ag (KQC35070.1); 64/85 AbyA3 AbsA3 AbmA3 B0F77_RS29710 231 hypothetical protein acyltransferase, Streptomyces olindensis (KDN76174.1); 65/78 AbyA4 AbsA4 AbmA4 B0F77_RS29715 357 alpha/beta hydrolase alpha/beta hydrolase, Actinomadura macra (WP_067456402.1); 55/68 AbyA5 AbsA5 AbmA5 nuclear transport factor 2 B0F77_RS29720 117 hypothetical protein, Planobispora rosea (WP_084780980.1); 38/67 - - - family protein B0F77_RS29725 4307 PKS I type I polyketide synthase, Streptomyces sp. 2112.2 (WP_093485656.1); 52/64 AbyB1 AbsB1 AbmB1 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// SDR family NAD(P)-dependent oxidoreductase, Streptomyces olivoreticuli B0F77_RS29020 4693 PKS I PKS I PKS I PKS I (WP_116210514.1); 54/65 B0F77_RS29025 - PKS I type I polyketide synthase, Streptomyces odonnellii (WP_046496891.1); 52/63 PKS I PKS I PKS I B0F77_RS29030 - PKS I modular polyketide synthase, Streptomyces neyagawaensis (BAW35659.1); 63/74 PKS I PKS I PKS I type I modular polyketide synthase, Streptomyces griseochromogenes B0F77_RS29035 - PKS I PKS I PKS I PKS I (ABV91286.1); 61/70 hypothetical protein N566_17825, partial, Streptomycetaceae bacterium MP113-05 B0F77_RS29040 - PKS I PKS I PKS I PKS I (EST35181.1); 66/74 B0F77_RS29045 - PKS I polyketide synthase, partial, Streptomyces sp. WM6391 (KKD10026.1); 65/78 PKS I PKS I PKS I

79 B0F77_RS29050 - PKS I polyketide synthase, partial, Streptomyces platensis (BAH67341.1); 67/75 PKS I PKS I PKS I SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. NL15-2K B0F77_RS29055 - PKS I PKS I PKS I PKS I (WP_124445724.1); 53/63 Polyketide synthase dehydratase, partial, Streptomyces sp. MnatMP-M27 B0F77_RS29060 - PKS I PKS I PKS I PKS I (SCG04427.1); 65/74 type I polyketide synthase, Streptacidiphilus neutrinimicus (WP_052442691.1); B0F77_RS29065 - PKS I PKS I PKS I PKS I 53/64 B0F77_RS29070 500 hypothetical protein hypothetical protein, Actinomadura sp. H3C3 (WP_131898125.1); 57/67 - - - TetR/AcrR family TetR/AcrR family transcriptional regulator, Frankia symbiont of Coriaria ruscifolia B0F77_RS29075 183 - AbsC2 - transcriptional regulator (WP_131786661.1); 76/87 nuclear transport factor 2 family protein, Frankia symbiont of Coriaria ruscifolia B0F77_RS29080 138 hypothetical protein - - - (WP_131786662.1); 85/90 multidrug efflux MFS drug resistance transporter, EmrB/QacA subfamily, Candidatus Frankia B0F77_RS29085 479 AbyD AbsD AbmD transporter californiensis (SBW22286.1); 76/87 LLM class flavin-dependent MsnO8 family LLM class oxidoreductase, Actinocrispum wychmicini B0F77_RS29090 340 AbyE AbsE AbmE1 oxidoreductase (WP_132113998.1); 53/71 B0F77_RS29095 398 cytochrome P450 cytochrome P450, Streptomyces sp. SCA2-2 (WP_129847673.1); 57/72 AbyX/AbyV AbsV/AbsX AbmV maleylpyruvate isomerase maleylpyruvate isomerase family mycothiol-dependent enzyme, Actinomadura B0F77_RS29100 256 - - - family protein fibrosa (WP_131760704.1); 40/56 AfsR/SARP family B0F77_RS29105 282 activator protein, Actinomadura sp. 6K520 (WP_131977283.1); 53/71 AbyI - AbmI transcriptional regulator B0F77_RS29110 139 Diels-Alderase hypothetical protein, Streptomyces sp. FXJ7.023 (WP_037772721.1); 55/66 AbyU AbsU AbmU 3-hydroxybutyryl-CoA 3-hydroxybutyryl-CoA dehydrogenase, Lechevalieria aerocolonigenes B0F77_RS29115 268 - - - dehydrogenase (WP_030470217.1); 59/74 ketoacyl-ACP synthase III, Saccharothrix sp. NRRL B-16314 (WP_081915703.1); B0F77_RS29120 448 ketoacyl-ACP synthase III - - - 72/81

80 Table S44. Predicted functions of ORFs in potential abyssomicin BGC from Kutzneria buriramensis DSM 45791 (NZ_QUNO01000013 and NZ_QUNO01000029).

Size Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog (aa) homolog BCF44_RS50005 291 hypothetical protein hypothetical protein, Actinoplanes regularis (WP_089291877.1); 74/82 - - - BCF44_RS50000 193 hypothetical protein transposase, Kutzneria sp. 744 (EWM10014.1); 81/87 - - - LuxR family transcriptional regulator, Frankia sp. Cc1.17 BCF44_RS49995 1027 hypothetical protein AbyH - AbmH (WP_071084446.1); 41/53 AfsR/SARP family BCF44_RS49990 253 activator protein, Rhodococcus yunnanensis (WP_072806089.1); 65/78 AbyI - AbmI transcriptional regulator HAD-IIIC family phosphatase, Micromonospora sp. RP3T BCF44_RS49985 625 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 (WP_107154962.1); 65/75 acyl carrier protein, Streptomyces sp. NRRL F-525 (WP_033287159.1); BCF44_RS49980 75 acyl carrier protein AbyA3 AbsA3 AbmA3 65/77 BCF44_RS49975 251 thioesterase thioesterase, Streptomyces sp. 4R-3d (TFI25382.1); 55/65 AbyT AbsN AbmT ABC transporter ATP-binding ABC transporter ATP-binding protein, Frankia coriariae BCF44_RS49970 519 AbyF4 AbsF4 AbmF4 protein (WP_047222767.1); 67/76 NADPH-dependent FMN NADPH-dependent FMN reductase, Kutzneria albida (WP_025355017.1); BCF44_RS49965 186 AbyZ AbsH1 AbmZ reductase 61/74 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Saccharothrix syringae BCF44_RS49960 352 - - AbmE2 oxidoreductase (WP_033434377.1); 70/81 BCF44_RS49955 65 ferredoxin ferredoxin, Streptomyces yokosukanensis (WP_067118731.1); 61/75 - AbsG2/AbsG1 AbmG TetR/AcrR family regulatory protein TetR, Frankia symbiont of Datisca glomerata BCF44_RS49950 201 - - - transcriptional regulator (AEH09834.1); 72/81 DHA2 family efflux MFS transporter permease subunit, Frankia coriariae BCF44_RS49945 477 MFS transporter AbyD AbsD AbmD (WP_047222768.1); 69/80 NtaA/DmoA family FMN- FMN-dependent oxidoreductase, nitrilotriacetate monooxygenase family, BCF44_RS49940 452 - - - dependent monooxygenase Frankia symbiont of Datisca glomerata (AEH09835.1); 71/81 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces sp. RTd22 BCF44_RS49935 395 - - - oxidoreductase (WP_063731414.1); 57/66 BCF44_RS49930 406 cytochrome P450 cytochrome P450, Saccharothrix syringae (WP_033434378.1); 62/77 AbyX/AbyV AbsV/AbsX AbmV MsnO8 family LLM class LLM class flavin-dependent oxidoreductase, Frankia alni BCF44_RS49925 336 AbyE AbsE AbmE1 oxidoreductase (WP_011601492.1); 55/65 BCF44_RS49920 286 ABC transporter permease peptide ABC transporter permease, Frankia coriariae (KLL11667.1); 70/79 AbyF3 AbsF3 AbmF3 BCF44_RS49915 308 ABC transporter permease ABC transporter permease, Frankia coriariae (KLL11700.1); 77/88 AbyF2 AbsF2 AbmF2 ABC transporter substrate- ABC-type transporter, periplasmic subunit, Frankia symbiont of Datisca BCF44_RS49910 550 AbyF1 AbsF1 AbmF1 binding protein glomerata (AEH09839.1); 65/76 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Saccharothrix syringae BCF44_RS49905 345 AbyA1 AbsA1 AbmA1 family protein (WP_033434375.1); 79/85 BCF44_RS49900 261 acyltransferase acyltransferas, Frankia sp. BMG5.30 (WP_076843553.1); 69/78 AbyA4 AbsA4 AbmA4

81 BCF44_RS49895 340 alpha/beta hydrolase alpha/beta hydrolase, Frankia sp. BMG5.30 (ONH34857.1); 65/75 AbyA5 AbsA5 AbmA5 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. MK-45 BCF44_RS49890 3837 PKS I PKS I PKS I PKS I (WP_126395712.1); 55/65 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// BCF44_RS33785 105 PKS I polyketide synthase, Actinoplanes sp. N902-109 (AGL15968.1); 45/55 PKS I PKS I PKS I type I polyketide synthase, Saccharothrix syringae (WP_033434373.1); BCF44_RS33790 3424 PKS I AbyB2 AbsB2 AbmB2 59/69 type I polyketide synthase, Saccharothrix syringae (WP_051766715.1); BCF44_RS33795 1332 PKS I AbyB3 AbsB3 AbmB3 68/75 hypothetical protein FrCorBMG51_12000, Frankia coriariae (KLL11361.1); BCF44_RS33800 125 Diels-Alderase AbyU AbsU AbmU 77/86

82 Table S45. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces sp. LHW50302 (NZ_QOIM01000040).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog DQ392_RS21910 950 PKS I polyketide synthase, partial, Candidatus Streptomyces philanthi (RCG25677.1); 90/93 - - - DQ392_RS21915 201 Diels-Alderase hypothetical protein, Candidatus Streptomyces philanthi (WP_114021297.1); 98/99 AbyU AbsU AbmU DQ392_RS21920 403 cytochrome P450 cytochrome P450, Candidatus Streptomyces philanthi (WP_114021298.1); 99/99 - - - DQ392_RS21925 253 methyltransferase methyltransferase, Candidatus Streptomyces philanthi (WP_114021299.1); 98/99 - - - DQ392_RS21930 347 3-oxoacyl-ACP synthase 3-oxoacyl-ACP synthase, Candidatus Streptomyces philanthi (WP_114021300.1); 99/99 - - - type I polyketide synthase, Candidatus Streptomyces philanthi (WP_114021301.1); DQ392_RS21935 1825 PKS I - - - 93/94 dTDP-glucose 4,6- dTDP-glucose 4,6-dehydratase, Candidatus Streptomyces philanthi (WP_114021302.1); DQ392_RS21940 323 - - - dehydratase 98/99 helix-turn-helix helix-turn-helix transcriptional regulator, Candidatus Streptomyces philanthi DQ392_RS21945 972 - - - transcriptional regulator (WP_114021303.1); 95/96 DUF2075 domain-containing DUF2075 domain-containing protein, Candidatus Streptomyces philanthi DQ392_RS21950 776 - - - protein (WP_114021304.1); 97/98

83 Table S46. Predicted functions of ORFs in potential abyssomicin BGC from Microbispora triticiradicis NEAU-HRDPA2-9 (NZ_QFZU02000171.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) ABC transporter ATP- ABC transporter ATP-binding protein, Streptosporangium subroseum DI270_RS29465 298 AbyF4 AbsF4 AbmF4 binding protein (WP_089206779.1); 76/81 DI270_RS29470 395 cytochrome P450 cytochrome P450, Streptomyces sp. Amel2xE9 (WP_027758724.1); 86/92 AbyX/AbyV AbsV/AbsX AbmV DI270_RS29475 68 ferredoxin ferredoxin-1, Streptomyces sp. NRRL F-6491 (KOX15570.1); 66/78 - AbsG1/AbsG2 AbmG DI270_RS29480 385 acyltransferase acyltransferase, Streptomyces sp. E14 (WP_009191675.1); 71/78 - AbsI - DI270_RS29485 401 cytochrome P450 cytochrome P450, Streptosporangium subroseum (WP_089206781.1); 85/91 AbyX/AbyV AbsV/AbsX AbmV DI270_RS29490 77 ferredoxin ferredoxin, Streptosporangium subroseum (WP_089206642.1); 87/91 - AbsG2/AbsG1 AbmG DI270_RS29495 332 aldo/keto reductase aldo/keto reductase, Streptosporangium subroseum (WP_089206643.1); 82/89 - AbsJ AbmJ hypothetical protein SAMN05216276_1006109, Streptosporangium DI270_RS29500 134 Diels-Alderase AbyU AbsU AbmU subroseum (SNS24121.1); 91/96 LuxR family LuxR family transcriptional regulator, Frankia sp. QA3 (WP_009738951.1); DI270_RS29505 933 AbyH - AbmH transcriptional regulator 54/66 TetR/AcrR family TetR/AcrR family transcriptional regulator, Microbispora rosea DI270_RS29510 195 - AbsC2 - transcriptional regulator (WP_076442332.1); 91/94 DI270_RS29515 475 MFS transporter MFS transporter, Microbispora sp. GKU 823 (WP_079317079.1); 88/92 AbyD AbsD AbmD AfsR/SARP family AfsR/SARP family transcriptional regulator, Microbispora sp. GKU 823 DI270_RS29520 252 AbyR/AbyI - AbmI transcriptional regulator (WP_079317077.1); 88/94

84 Table S47. Predicted functions of ORFs in abyssomicin BGC from Micromonospora wenchangensis CCTCC AA 2012002 (NZ_MZMV01000061.1 and NZ_MZMV01000027.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) SARP family transcriptional DNA-binding SARP family transcriptional activator, Actinokineospora B5D80_RS26560 251 AbyR/AbyI - AbmI regulator auranticolor (PPK71426.1); 74/82 B5D80_RS26565 397 cytochrome P450 cytochrome P450, Verrucosispora (WP_013733063.1); 82/90 AbyX/AbyV AbsV/AbsX AbmV LuxR family transcriptional LuxR family transcriptional regulator, Verrucosispora maris AB-18-032 B5D80_RS26570 898 AbyH - AbmH regulator (AEK75494.1); 68/77 Chain A, Abyu – Wildtype, Verrucosispora maris AB-16-032 (5DYV_A); B5D80_RS26575 141 Diels-Alderase AbyU AbsU AbmU 85/91 YD repeat protein, Verrucosispora maris AB-18-032 (AEK75496.1); B5D80_RS26580 617 RHS repeat protein AbyK - - 75/82 methoxymalonyl-ACP biosynthesis protein FkbH, Micromonospora B5D80_RS26585 1040 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 wenchangensis (OWV01453.1); 99/100 B5D80_RS26590 75 acyl carrier protein acyl carrier protein, Verrucosispora (WP_043723886.1); 75/82 AbyA3 AbsA3 AbmA3 B5D80_RS26595 250 acyltransferase Acyltransferase, Verrucosispora maris (WP_013733055.1); 83/91 AbyA4 AbsA4 AbmA4 B5D80_RS26600 355 alpha/beta hydrolase alpha/beta hydrolase, Verrucosispora maris (WP_013733054.1); 79/87 AbyA5 AbsA5 AbmA5 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// modular polyketide synthase, Verrucosispora maris AB-18-032 B5D80_RS17105 2437 PKS I AbyB1 AbsB1 AbmB1 (AEB44393.1); 71/77 type I polyketide synthase, Verrucosispora maris (WP_013733052.1); B5D80_RS17110 2053 PKS I AbyB2 AbsB2 AbmB2 73/80 acyltransferase domain-containing protein, Verrucosispora maris B5D80_RS17115 998 PKS I AbyB3 AbsB3 AbmB3 (WP_013733051.1); 77/84 TetR/AcrR family TetR/AcrR family transcriptional regulator, Verrucosispora maris B5D80_RS17120 230 AbyC - AbmC transcriptional regulator (WP_013733050.1); 88/92 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Verrucosispora B5D80_RS17125 474 AbyD AbsD AbmD transporter permease subunit (WP_013733049.1); 86/92 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Verrucosispora B5D80_RS17130 336 AbyE AbsE AbmE1 oxidoreductase (WP_013733048.1): 82/89 ABC transporter substrate- ABC transporter substrate-binding protein, Verrucosispora B5D80_RS17135 566 AbyF1 AbsF1 AbmF1 binding protein (WP_013733047.1); 75/86 B5D80_RS17140 311 ABC transporter permease ABC transporter permease, Verrucosispora (WP_013733046.1); 82/88 AbyF2 AbsF2 AbmF2 ABC transporter permease, Verrucosispora sp. FIM060022 B5D80_RS17145 283 ABC transporter permease AbyF3 AbsF3 AbmF3 (WP_126713145.1); 83/87 ABC transporter ATP-binding ABC transporter ATP-binding protein, Verrucosispora maris B5D80_RS17150 539 AbyF4 AbsF4 AbmF4 protein (WP_013733044.1); 80/87 B5D80_RS17155 396 cytochrome P450 cytochrome P450, Verrucosispora maris (WP_013733043.1); 83/86 AbyV/AbyX AbsV/AbsX AbmV B5D80_RS17160 79 ferredoxin-1 Ferredoxin, Verrucosispora sp. FIM060022 (WP_126713142.1); 68/77 AbyW AbsG2/AbsG1 AbmG

85 FMN reductase (NADPH), Streptomyces sp. A244 (WP_107460035.1); B5D80_RS17165 203 FMN reductase (NADPH) AbyZ AbsH1 AbmZ 81/86 B5D80_RS17170 303 thioesterase Thioesterase, Verrucosispora (P_081476081.1); 70/76 AbyT AbsN AbmT

86 Table S48. Predicted functions of ORFs in potential abyssomicin BGC from Micromonospora sp. RP3T (PYPS01000018 and PYPS01000002.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog C8054_RS16510 134 Diels-Alderase hypothetical protein, Streptomyces rimosus (WP_033030402.1); 37/58 AbyU AbsU AbmU C8054_RS16515 947 hypothetical protein hypothetical protein, Sphaerisporangium sp. LHW63015 (WP_113983256.1); 50/59 - - - C8054_RS16520 413 cytochrome P450 cytochrome P450, Streptomyces sp. ICBB 8177 (WP_109446503.1); 66/79 AbyX/AbyV AbsV/AbsX AbmV C8054_RS16525 68 ferredoxin ferredoxin, Nocardia sp. BMG111209 (WP_026343320.1); 52/64 - AbsG1 AbmG LuxR family transcriptional C8054_RS16530 940 regulatory LuxR family protein, Herbihabitans rhizosphaerae (RZS36569.1); 39/55 - - - regulator DHA2 family efflux MFS transporter permease subunit, Frankia sp. Cc1.17 C8054_RS16535 494 MFS transporter AbyD AbsD AbmD (WP_071090374.1); 49/65 TIGR03564 family F420- TIGR03564 family F420-dependent LLM class oxidoreductase, Amycolatopsis C8054_RS16540 316 dependent LLM class - - - tolypomycina (WP_091310088.1); 65/78 oxidoreductase C8054_RS16545 358 alpha/beta hydrolase alpha/beta hydrolase, Actinocrispum wychmicini (WP_132114014.1); 59/72 AbyA5 AbsA5 AbmA5 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// C8054_01980 - PKS I acyl transferase domain-containing protein, Streptomyces sp. 70 (PIG77230.1); 60/70 PKS I PKS I PKS I 3-oxoacyl-ACP synthase III family protein, Amycolatopsis sp. CA-126428 C8054_01985 344 3-oxoacyl-ACP synthase AbyA1 AbsA1 AbmA1 (WP_103342534.1); 59/74 C8054_01990 269 acyltransferase acyltransferase, Actinomadura pelletieri (WP_121438112.1); 62/71 AbyA4 AbsA4 AbmA4 C8054_01995 487 hypothetical protein hypothetical protein, Micromonospora wenchangensis (WP_088642273.1); 50/64 - - - drug resistance transporter, EmrB/QacA subfamily, partial, Streptomyces sp. C8054_02000 488 hypothetical protein AbyD AbsD AbmD SolWspMP-5a-2 (SCD36213.1); 43/68 TetR/AcrR family C8054_02005 184 TetR/AcrR family transcriptional regulator, Frankia sp. QA3 (WP_009742630.1); 51/65 - - - transcriptional regulator C8054_02010 140 hypothetical protein hypothetical protein, Micromonospora auratinigra (WP_091660051.1); 67/83 - - - C8054_02015 343 methyltransferase methyltransferase, Streptomyces griseorubiginosus (WP_123763216.1); 42/59 - - - C8054_02020 255 thioesterase thioesterase, Actinomadura pelletieri (WP_121438108.1); 58/70 AbyT AbsN AbmT C8054_02025 258 activator protein activator protein, Micromonospora endolithica (WP_120723474.1); 61/74 AbyI/AbyR - AbmI methoxymalonyl-ACP C8054_02030 630 HAD-IIIC family phosphatase, Actinomadura pelletieri (WP_121438114.1); 65/76 AbyA2 AbsA2 AbmA2 biosynthesis protein FkbH C8054_02035 80 acyl carrier protein acyl carrier protein, Actinomadura sp. 6K520 (WP_131977265.1); 55/76 AbyA3 AbsA3 AbmA3 methionine methionine adenosyltransferase, Actinoplanes sp. N902-109 (WP_015623988.1); C8054_02040 395 - - - adenosyltransferase 89/95 FAD-dependent C8054_02045 385 ferredoxin reductase, Actinoplanes sp. TFC3 (WP_067499520.1); 75/82 - - - oxidoreductase

87 C8054_02050 407 cytochrome P450 cytochrome P450, Amycolatopsis kentuckyensis (WP_086841038.1); 61/73 AbyX/AbyV AbsX/AbsV AbmV

88 Table S49. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces monomycini NRRL B-24309 (NZ_KL571104.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog helix-turn-helix transcriptional helix-turn-helix transcriptional regulator, Streptomyces lavendulae HY87_RS0129240 889 - - - regulator (WP_030241329.1); 53/61 helix-turn-helix transcriptional regulator, Streptomyces lavendulae HY87_RS0129245 1131 hypothetical protein - - - (WP_030241327.1); 57/68 AfsR/SARP family transcriptional HY87_RS0129250 245 activator protein, Kutzneria buriramensis (WP_116181646.1); 50/66 - - - regulator hypothetical protein, Streptomyces caatingaensis HY87_RS1000000143920 169 Diels-Alderase AbyU AbsU AbmU (WP_049718340.1); 44/65

89 Table S50. Predicted functions of ORFs in potential BGC from Streptomyces sp. MUSC 14 (NZ_MLYN01000052).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. QA3 BIV25_RS31795 320 - - - oxidoreductase (WP_009742601.1); 63/76 BIV25_RS31800 185 DinB family protein uncharacterized protein DUF664, Streptomyces sp. 67 (RED71639.1); 86/90 - - - GNAT family N-acetyltransferase, Streptomyces sp. BK161 (WP_133927666.1); BIV25_RS47940 41 GNAT family N-acetyltransferase - - - 78/87 BIV25_RS31805 508 cytochrome P450 cytochrome P450, Streptomyces sp. MUSC 1 (WP_079173711.1); 92/94 - - - DUF2029 domain-containing protein, Streptomyces sp. MUSC 1 BIV25_RS31810 406 DUF2029 domain-containing protein - - - (WP_107471405.1); 95/96 3-deoxy-7-phosphoheptulonate 3-deoxy-7-phosphoheptulonate synthase class II, Streptomyces tateyamensis BIV25_RS31815 473 - - - synthase class II (WP_110665468.1); 75/84 3-hydroxybutyryl-CoA 3-hydroxybutyryl-CoA dehydrogenase, Frankia sp. BMG5.36 (OHV43725.1); BIV25_RS31820 285 - - - dehydrogenase 58/77 beta-ketoacyl-ACP synthase III, Amycolatopsis sp. 8-3EHSu BIV25_RS31825 344 ketoacyl-ACP synthase III - - - (WP_130478882.1); 70/81 crotonyl-CoA carboxylase/reductase, Actinomadura macra (WP_067467652.1); BIV25_RS31830 450 crotonyl-CoA carboxylase/reductase - - - 77/86 BIV25_RS31835 255 thioesterase thioesterase, Streptomyces sp. MA5143a (WP_107466330.1); 62/73 - - - pyridoxamine 5'-phosphate oxidase pyridoxamine 5'-phosphate oxidase family protein, Streptomyces iranensis BIV25_RS31840 173 - - - family protein (WP_044580008.1); 77/84 BIV25_RS31845 3932 PKS I type I polyketide synthase, Streptomyces iranensis (WP_044580009.1); 80/87 - - - BIV25_RS31850 1360 PKS I type I polyketide synthase, Streptomyces iranensis (WP_044580010.1); 82/88 - - - BIV25_RS31855 411 cytochrome P450 cytochrome P450, Saccharothrix syringae (WP_033431229.1); 66/78 - - - nuclear transport factor 2 family nuclear transport factor 2 family protein, Streptomyces cattleya BIV25_RS31860 119 - - - protein (WP_014627233.1); 56/76 hypothetical protein, Streptomyces sp. E5N91 SAI-083 (WP_123627591.1); BIV25_RS31865 139 Diels-Alderase AbyU AbsU AbmU 61/78 FAD-dependent monooxygenase, Saccharopolyspora sp. 16K309 BIV25_RS31870 412 monooxygenase - - - (WP_132674765.1); 55/65 BIV25_RS31875 445 salicylate synthase salicylate synthetase, Amycolatopsis xylanica (SDW43103.1); 68/79 - - - BIV25_RS31880 317 hypothetical protein malonyl transferase, Streptomyces uncialis (WP_073785742.1); 39/57 - - - BIV25_RS31885 355 arylcarboxylate reductase arylcarboxylate reductase, Streptomyces sp. PRh5 (EXU64039.1); 62/73 - - - BIV25_RS31890 385 cytochrome P450 cytochrome P450, Actinobacteria bacterium (PZM89993.1); 43/56 - - - flavin reductase family protein, Rhodoplanes sp. Z2-YC6860 BIV25_RS31895 203 flavin reductase family protein - - - (WP_068017711.1); 51/66 helix-turn-helix domain-containing helix-turn-helix domain-containing protein, Streptomyces phaeochromogenes BIV25_RS31900 377 - - - protein (WP_079053449.1); 68/74

90 helix-turn-helix transcriptional helix-turn-helix transcriptional regulator, Streptomyces iranensis BIV25_RS31905 918 - - - regulator (WP_044580016.1); 64/75 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Pseudonocardia acaciae BIV25_RS31910 198 - - - regulator (WP_051579483.1); 55/69 DHA2 family efflux MFS transporter permease subunit, Kutzneria buriramensis BIV25_RS31915 564 MFS transporter - - - (WP_116174721.1); 54/73

91 Table S51. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces niveus NRRL 2466 (NZ_MDCR01000040).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog BHU15_RS06405 388 acyltransferase acyltransferase, Streptomyces luteocolor (WP_069885825.1); 49/65 - AbsI - helix-turn-helix transcriptional regulator, Streptomyces sp. 4R-3d BHU15_RS06410 923 helix-turn-helix transcriptional regulator AbyH - AbmH (TFI22095.1); 99/99 BHU15_RS06415 253 AfsR/SARP family transcriptional regulator activator protein, Streptomyces sp. SCA2-2 (WP_129847683.1); 63/74 AbyI - AbmI TetR/AcrR family transcriptional regulator, Sinosporangium album BHU15_RS06420 195 TetR/AcrR family transcriptional regulator - AbsC2 - (WP_093167074.1); 74/84 BHU15_RS06425 499 MFS transporter MFS transporter, Sinosporangium album (WP_093167076.1); 81/88 AbyD AbsD AbyD ABC transporter substrate-binding protein, Streptomyces sp. 4R-3d BHU15_RS06430 321 hypothetical protein AbyF1 AbsF1 AbmF1 (TFI25403.1); 99/99 ABC transporter permease, Streptomyces sp. SCA2-2 BHU15_RS06435 282 ABC transporter permease AbyF2 AbsF2 AbsmF2 (WP_129847675.1); 69/82 amidohydrolase family protein, Streptomyces sp. SCA2-2 BHU15_RS06440 410 amidohydrolase family protein - - AbmM (WP_129847676.1); 62/71 BHU15_RS06445 304 ABC transporter permease ABC transporter permease, Streptomyces sp. 4R-3d (TFI25375.1); 98/98 AbyF3 AbsF3 AbmF3 ABC transporter ATP-binding protein, Streptomyces sp. 4R-3d BHU15_RS06450 620 ABC transporter ATP-binding protein AbyF4 AbsF4 AbmF4 (TFI25374.1); 99/99 BHU15_RS06455 217 Diels-Alderase AbmU, Streptomyces koyangensis (AVI57412.1); 53/68 AbyU AbsU AbmU

92 Table S52. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces sp. NL15-2K (NZ_BHXA01000189.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) SDR family NAD(P)-dependent oxidoreductase, Streptomyces SNL152K_RS52860 1358 PKS I PKS I PKS I PKS I griseocarneus (WP_121797418.1); 50/61 type I polyketide synthase, Streptomyces formicae (WP_098241246.1); SNL152K_RS52865 2156 PKS I PKS I PKS I PKS I 54/64 modular polyketide synthase, Streptomyces sp. RK95-74 (BAW35608.1); SNL152K_RS52870 1727 PKS I PKS I PKS I PKS I 49/61 cytochrome P450, Streptomyces sp. WMMB 322 (WP_055484149.1); SNL152K_RS52875 409 cytochrome P450 AbyX/AbyV AbsV/AbsX AbmV 55/68 SNL152K_RS52880 63 ferredoxin ferredoxin, Thermostaphylospora chromogena (WP_093260901.1); 61/75 - AbsG1/AbsG2 AbmG SNL152K_RS52885 145 Diels-Alderase hypothetical protein, Streptomyces geranii (WP_105971044.1); 58/72 AbyU AbsU AbmU SNL152K_RS52890 267 acyltransferase acyltransferase, Streptomyces olindensis (KDN76174.1); 60/72 AbyA4 AbsA4 AbmA4 SNL152K_RS52895 390 alpha/beta fold hydrolase alpha/beta hydrolase, Streptomyces geranii (WP_107503113.1); 75/80 AbyA5 AbsA5 AbmA5 SNL152K_RS52900 354 hypothetical protein hypothetical protein, Streptomyces geranii (WP_105971045.1); 92/95 - - - SNL152K_RS52905 151 Diels-Alderase hypothetical protein, Streptomyces geranii (WP_105971044.1); 91/95 AbyU AbsU AbmU SNL152K_RS52910 72 hypothetical protein hypothetical protein, Streptomyces geranii (WP_105971043.1); 80/87 - - - SNL152K_RS52915 69 hypothetical protein hypothetical protein, Streptomyces geranii (WP_105971042.1); 93/98 - - - acyl-CoA carboxylase acyl-CoA carboxylase subunit beta, Streptomyces sp. SYSU K10008 SNL152K_RS52920 520 - - - subunit beta (WP_128380899.1); 81/89

93 Table S53. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces sp. NRRL F-525 (NZ_JNXE01000068).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog OO69_RS46840 174 Diels-Alderase hypothetical protein, Streptomyces caatingaensis (WP_049718340.1); 34/47 AbyU AbsU AbmU 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Lentzea kentuckyensis OO69_RS46845 343 AbyA1 AbsA1 AbmA1 protein (WP_086666305.1); 66/81 HAD-IIIC family phosphatase, Actinocrispum wychmicini (WP_132116038.1); OO69_RS46850 634 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 62/73 OO69_RS46855 76 acyl carrier protein acyl carrier protein, Streptomyces sp. NRRL F-5123 (WP_031525362.1); 72/89 AbyA3 AbsA3 AbmA3 OO69_RS46860 228 acyltransferase acyltransferase, Streptomyces kanamyceticus (WP_055549000.1); 61/77 AbyA4 AbsA4 AbmA4 OO69_RS46865 364 alpha/beta hydrolase alpha/beta hydrolase, Actinocrispum wychmicini (WP_132114014.1); 62/74 AbyA5 AbsA5 AbmA5 OO69_RS46870 268 thioesterase thioesterase, Actinoplanes sp. N902-109 (WP_051167423.1); 54/62 AbyT AbsN AbmT OO69_RS46875 1637 PKS I type I polyketide synthase, Streptomyces sp. MBT76 (WP_058042044.1); 62/71 PKS I PKS I PKS I

Table S54. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces sp. NRRL F-525 (NZ_JNXE01000075).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog OO69_RS47325 497 hypothetical protein hypothetical protein, Actinomadura macra (WP_067456441.1); 51/62 - - - OO69_RS47330 251 thioesterase thioesterase, Streptomyces sp. NEAU-S7GS2 (AWN25442.1); 65/79 AbyT AbsN AbmT AfsR/SARP family transcriptional OO69_RS47335 255 activator protein, Actinomadura chibensis (WP_067904593.1); 60/73 AbyI - AbmI regulator regulatory LuxR family protein, Herbihabitans rhizosphaerae (RZS36569.1); OO69_RS47345 1011 LuxR family transcriptional regulator - - - 42/57 OO69_RS47350 184 Diels-Alderase hypothetical protein, Streptomyces sp. NL15-2K (WP_124445685.1); 40/57 AbyU AbsU AbmU DHA2 family efflux MFS transporter permease subunit, Streptomyces sp. OO69_RS47355 518 MFS transporter AbyD AbsD AbyD FXJ1.172 (WP_107304187.1); 57/75

94 Table S55. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces sp. NRRL F-5126 (NZ_JOFZ01000007).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog type I polyketide synthase PikAI, Streptomyces sp. SolWspMP-5a-2 (SCD36199.1); IH48_RS33370 555 PKS I PKS I PKS I PKS I 87/92 drug resistance transporter, EmrB/QacA subfamily, partial, Streptomyces sp. SolWspMP- IH48_RS0116245 537 MFS transporter AbyD AbsD AbyD 5a-2 (SCD36213.1); 92/94 DHA2 family efflux MFS transporter permease subunit, Streptomyces sp. SolWspMP-5a- IH48_RS0116250 510 MFS transporter AbyD AbsD AbyD 2 (WP_093830605.1); 91/95 TetR/AcrR family TetR/AcrR family transcriptional regulator, Streptomyces sp. SolWspMP-5a-2 IH48_RS0116255 214 - - - transcriptional regulator (WP_093830608.1); 90/95 IH48_RS0116260 494 hypothetical protein hypothetical protein, Streptomyces sp. SolWspMP-5a-2 (WP_093830610.1); 90/93 - - - hypothetical protein GA0115242_12174, Streptomyces sp. SolWspMP-5a-2 IH48_RS0116265 133 Diels-Alderase AbyU AbsU AbmU (SCE08777.1); 90/94 IH48_RS0116270 76 hypothetical protein hypothetical protein, Streptomyces sp. SolWspMP-5a-2 (WP_093830614.1); 76/81 - - - 3-oxoacyl-ACP synthase 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. SolWspMP-5a-2 IH48_RS0116275 343 AbyA1 AbsA1 AbmA1 III family protein (WP_093830729.1); 97/99 AfsR/SARP family IH48_RS0116280 265 activator protein, Nonomuraea polychroma (WP_127931360.1); 54/69 AbyI - AbmI transcriptional regulator IH48_RS0116285 373 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces sp. SolWspMP-5a-2 (WP_093830618.1); 90/94 AbyA5 AbsA5 AbmA5 IH48_RS0116290 1519 PKS I type I polyketide synthase, Streptomyces sp. SolWspMP-5a-2 (WP_093830620.1); 91/94 - - - IH48_RS0116295 65 ferredoxin ferredoxin, Streptomyces sp. SolWspMP-5a-2 (WP_093830624.1); 88/95 - AbsG1 AbmG IH48_RS0116300 410 cytochrome P450 cytochrome P450, Streptomyces sp. SolWspMP-5a-2 (WP_093830626.1); 92/95 AbyX/AbyV AbsV/AbsX AbmV IH48_RS0116305 273 thioesterase thioesterase, Streptomyces sp. SolWspMP-5a-2 (WP_093830628.1); 90/93 AbyT AbsN AbmT

95 Table S56. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces sp. NRRL F-5755 (NZ_LGCW01000306).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog ADK86_RS35070 435 hypothetical protein hypothetical protein, Streptomyces albus (WP_060732989.1); 99/99 - - - ADK86_RS35075 433 MFS transporter MFS transporter, Streptomyces albus (WP_060732990.1); 99/99 - - - hypothetical protein ADL21_37760, Streptomyces albus subsp. albus (KWT56726.1); ADK86_RS35080 174 Diels-Alderase AbyU AbsU AbmU 98/98 ADK86_RS35085 448 MFS transporter MFS transporter, Streptomyces albus (WP_060732991.1); 99/99 - - - CGNR zinc finger domain- CGNR zinc finger domain-containing protein, Streptomyces sp. WAC 06725 ADK86_RS35090 173 - - - containing protein (RSO35445.1); 99/100 ADK86_RS35095 981 type I polyketide synthase type I polyketide synthase, Streptomyces albus (WP_060732992.1); 96/97 - - - ADK86_RS35100 402 FAD-dependent oxidoreductase FAD-dependent oxidoreductase, Streptomyces rimosus (WP_030643530.1); 99/99 - - - ADK86_RS35105 255 thioesterase thioesteras, Streptomyces albus (WP_060732994.1); 98/99 - - - (2,3-dihydroxybenzoyl)adenylate 2,3-dihydroxybenzoate--AMP ligase, Streptomyces griseoflavus (KOG53532.1); ADK86_RS35110 572 - - - synthase 97/97 ADK86_RS35115 77 acyl carrier protein acyl carrier protein, Streptomyces rimosus (WP_030643536.1); 99/100 - - - ADK86_RS35120 358 hypothetical protein hypothetical protein, Streptomyces albus (WP_060732996.1); 98/98 - - -

Table S57. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces sp. NRRL S-31 (NZ_JOCB01000102.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog IF37_RS0131380 403 cytochrome P450 cytochrome P450, Frankia sp. Cc1.17 (WP_071083429.1); 73/81 - - - IF37_RS0131385 181 Diels-Alderase hypothetical protein, Frankia sp. Cc1.17 (WP_131803042.1); 62/72 AbyU AbsU AbmU hypothetical protein CLV40_111123, Actinokineospora auranticolor IF37_RS0131390 129 Diels-Alderase AbyU AbsU AbmU (PPK66159.1); 60/76 IF37_RS0131395 342 3-oxoacyl-ACP synthase III family protein 3-oxoacyl-ACP synthase, Frankia sp. Cc1.17 (OHV40305.1); 76/85 - - - IF37_RS0131400 136 hypothetical protein - - - - IF37_RS0131405 - ABC transporter ATP-binding protein - - - - PAS domain-containing protein, Kitasatospora sp. OK780 IF37_RS0131410 792 PAS domain S-box protein - - - (WP_100891745.1); 57/68

96 Table S58. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces sp. NRRL WC-3742 (NZ_JOCF01000060.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Streptomyces sp. CB03911 IH61_RS0128745 213 AbyC - AbmC regulator (WP_073928463.1); 87/95 alpha/beta hydrolase, Streptomyces sp. CB03911 (WP_079198449.1); IH61_RS0128750 320 alpha/beta hydrolase - - - 78/86 ABC transporter substrate- ABC transporter substrate-binding protein, Streptacidiphilus sp. DSM IH61_RS0128755 577 AbyF1 AbsF1 AbmF1 binding protein 106435 (WP_111490404.1); 76/84 ABC transporter permease, Streptomyces sp. CB03911 IH61_RS0128760 311 ABC transporter permease AbyF2 AbsF2 AbmF2 (WP_073928465.1); 90/95 ABC transporter permease, Streptomyces sp. CB03911 IH61_RS0128765 269 ABC transporter permease AbyF3 AbsF3 AbmF3 (WP_073928702.1); 87/93 ABC transporter ATP-binding ABC transporter ATP-binding protein, Streptacidiphilus sp. DSM IH61_RS0128770 561 AbyF4 AbsF4 AbmF4 protein 106435 (WP_111490407.1); 79/86 NtaA/DmoA family FMN- LLM class flavin-dependent oxidoreductase, Streptomyces sp. IH61_RS0128775 373 - - - dependent monooxygenase CB03911 (WP_073928466.1); 90/93 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptacidiphilus sp. DSM IH61_RS0128780 340 AbyE AbsE AbmE1 oxidoreductase 106435 (WP_111490409.1); 86/89 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptacidiphilus sp. DSM IH61_RS0128785 347 - - AbmE2 oxidoreductase 106435 (WP_111490410.1); 85/93 acyltransferase domain-containing protein, Streptacidiphilus sp. DSM IH61_RS0128790 1061 PKS I AbyB3 AbsB3 AbmB3 106435 (WP_111490411.1); 81/86 SDR family NAD(P)-dependent oxidoreductase, Streptacidiphilus sp. IH61_RS46315 555 PKS I AbyB2 AbyB2 AbmB2 DSM 106435 (WP_114914558.1); 77/82 hypothetical protein, Streptacidiphilus sp. DSM 106435 IH61_RS44985 2041 PKS I AbyB1 AbyB1 AbmB1 (WP_114914555.1); 81/88 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Streptacidiphilus sp. DSM IH61_RS0128805 343 AbyA1 AbsA1 AbmA1 protein 106435 (WP_111492779.1); 85/90 hypothetical protein, Streptomyces sp. CB03911 (WP_073928710.1); IH61_RS0128810 125 Diels-Alderase AbyU AbsU AbmU 86/92 IH61_RS0128815 399 cytochrome P450 cytochrome, Streptomyces sp. CB03911 (OKI12689.1); 88/93 AbyX/AbyV AbsV/AbsX AbmV IH61_RS0128820 79 ferredoxin ferredoxin, Streptomyces sp. CB03911 (WP_073928505.1); 74/83 - AbsG2/AbsG1 AbmG DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, IH61_RS0128825 480 AbyD AbsD AbyD transporter permease subunit Streptacidiphilus sp. DSM 106435 (WP_111492776.1); 87/93 acyltransferase, Streptomyces sp. CB03911 (WP_073928506.1); IH61_RS0128830 384 acyltransferase - AbsI - 77/86 aldo/keto reductase, Streptomyces sp. CB03911 (WP_073928507.1); IH61_RS0128835 332 aldo/keto reductase - AbsJ AbmJ 90/93 AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Streptacidiphilus sp. DSM IH61_RS0128840 272 AbyI/AbyR - AbmI regulator 106435 (WP_111492773.1); 89/93 LuxR family transcriptional LuxR family transcriptional regulator, Streptacidiphilus sp. DSM IH61_RS0128845 618 AbyH - AbmH regulator 106435 (WP_114914553.1); 66/75 acyltransferase, Streptomyces sp. CB03911 (WP_073928512.1); IH61_RS0128850 288 acyltransferase AbyA4 AbsA4 AbmA4 80/85

97 alpha/beta hydrolase, Streptomyces sp. CB03911 (WP_073928513.1); IH61_RS0128855 362 alpha/beta hydrolase AbyA5 AbsA5 AbmA5 84/91 AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Streptomyces sp. CB03911 IH61_RS0128860 298 AbyI - AbmI regulator (WP_073928514.1); 76/84 IH61_RS0128865 254 thioesterase thioesterase, Streptomyces sp. CB03911 (WP_079198461.1); 72/78 AbyT AbsN AbmT

98 Table S59. Predicted functions of ORFs in potential tetronomycin BGC from Streptomyces olindensis DAUFPE 5622 (JJOH01000019.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog DF19_2179 glucose-1-phosphate glucose-1-phosphate adenylyltransferase, Streptomyces sp. Go-475 (WP_114256683.1); 406 - - - 5 adenylyltransferase 99/100 DF19_2180 383 glycosyl transferase family 1 glycogen synthase, Streptomyces sp. Go-475 (WP_114256682.1); 99/99 - - - 0 DF19_2180 245 hypothetical protein (2Fe-2S)-binding protein, Streptomyces sp. Go-475 (WP_114257751.1); 85/86 - - - 5 DF19_2181 414 membrane protein hypothetical protein, Streptomyces sp. Go-475 (WP_114256681.1); 86/88 - - - 0 DF19_2181 424 peptidase peptidase, Streptomyces sp. Go-475 (WP_114256680.1); 93/96 - - - 5 DF19_2182 6-phosphogluconate NADP-dependent phosphogluconate dehydrogenase, Streptomyces sp. Go-475 479 - - - 0 dehydrogenase (WP_114256679.1); 99/99 DF19_2182 114 acetyltransferase N-acetyltransferase, Streptomyces sp. Go-475 (WP_114256678.1); 92/95 - - - 5 DF19_2183 aspartate 1-decarboxylase 139 aspartate 1-decarboxylase, Streptomyces sp. Go-475 (WP_114256677.1); 99/99 - - - 0 subunit alpha DF19_2183 75 hypothetical protein hypothetical protein, Streptomyces sp. 57 (WP_121408886.1); 47/62 - - - 5 DF19_2184 helix-turn-helix transcriptional regulator, Streptomyces sp. CNH099 (WP_078627912.1); 842 hypothetical protein - - - 0 62/75 DF19_2184 263 oleoyl-ACP hydrolase thioesterase, Streptomyces sp. CNZ306 (WP_100303313.1); 79/84 - - - 5 DF19_2185 75 acyl carrier protein acyl carrier protein, Streptomyces sp. CNH099 (WP_027756637.1); 89/96 - - - 0 DF19_2185 278 acyltransferase acyltransferase, Streptomyces sp. WAC 06738 (WP_125933459.1); 82/90 - - - 5 DF19_2186 4968 PKS I type I polyketide synthase, Streptomyces sp. CMB-StM0423 (WP_101426746.1); 73/79 - - - 0 DF19_2186 223 PKS I DedA family protein, Streptomyces sp. CNS335 (WP_018844985.1); 77/88 - - - 5 DF19_2187 173 Diels-Alderase hypothetical protein AA958_00640, Streptomyces sp. CNQ-509 (AKH80919.1); 67/77 AbyU AbsU AbmU 0 DF19_2187 500 PKS I hypothetical protein, Streptomyces sp. WAC 06738 (WP_125933460.1); 83/89 - - - 5 DF19_2188 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. WAC 06738 1582 PKS I - - - 0 (WP_125933461.1); 73/80 DF19_2188 146 PKS I hypothetical protein, Streptomyces sp. CNQ329 (WP_027774440.1); 76/84 - - - 5 DF19_2189 304 PKS I erythromycin 3''-O-methyltransferase, Streptomyces sp. CNZ306 (PJJ38656.1); 85/93 - - - 0 DF19_2189 1664 PKS I type I polyketide synthase, Streptomyces sp. CNT371 (WP_027746214.1); 77/83 - - - 5

99 DF19_2190 3666 PKS I type I polyketide synthase, Streptomyces sp. CNQ-509 (WP_047014289.1); 76/81 - - - 0 DF19_2190 3828 PKS I type I polyketide synthase, Streptomyces sp. CNQ-509 (WP_047014291.1); 70/79 - - - 5 DF19_2191 463 enterotoxin FAD-dependent oxidoreductase,Streptomyces sp. CNQ329 (WP_027770074.1); 85/89 - - - 0 DF19_2191 73 hypothetical protein ferredoxin, Streptomyces sp. CNH099 (WP_027757646.1); 73/83 - - - 5 DF19_2192 400 cytochrome P450 cytochrome P450, Streptomyces sp. CNZ306 (PJJ38667.1); 92/94 - - - 0 DF19_2192 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. CNQ-509 (WP_047014295.1); 342 3-oxoacyl-ACP synthase - - - 5 87/95 DF19_2193 MarR family transcriptional MarR family transcriptional regulator, Actinopolyspora mzabensis (WP_092625240.1); 173 - - - 0 regulator 55/71 DF19_2193 methoxymalonyl-ACP 632 HAD-IIIC family phosphatase, Streptomyces sp. CNH099 (WP_027757643.1); 85/91 - - - 5 biosynthesis protein FkbH DF19_2194 345 hypothetical protein alpha/beta fold hydrolase, Streptomyces sp. CNQ-509 (WP_047014297.1); 75/84 - - - 0 DF19_2194 543 hypothetical protein anibiotic ABC transporter, Plantactinospora sp. CNZ321 (WP_130464162.1); 50/67 - - - 5 DF19_2195 ABC transporter ATP-binding 306 ABC transporter ATP-binding protein, Rhodococcus sp. S2-17 (WP_109331707.1); 70/80 - - - 0 protein DF19_2195 256 activator protein activator protein, Streptomyces sp. CMB-StM0423 (AUH44525.1); 89/93 - - - 5 DF19_2196 type I polyketide synthase-related protein, Streptomyces sp. NRRL 11266 (BAE93739.1); 776 hypothetical protein - - - 0 66/74

100 Table S60. Predicted functions of ORFs in quartromicin BGC from Amycolatopsis orientalis Q427-8 (JF970188.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog QmnB 471 propionyl-CoA carboxylase acyl-CoA carboxylase subunit beta, Amycolatopsis albispora (WP_113696554.1); 97/98# - - - QmnC 251 thioesterase thioesterase, Amycolatopsis albispora (WP_113696553.1); 95/98 - - - 2-oxoacid dehydrogenase, QmnD4 322 alpha/beta hydrolase, Amycolatopsis albispora (WP_113696552.1); 90/93 - - - acyltransferase QmnA1 5924 PKS I type I polyketide synthase, Streptomyces cellostaticus (WP_067002540.1); 54/64 - - - SDR family NAD(P)-dependent oxidoreductase, Amycolatopsis albispora (WP_113696551.1); QmnA2 1771 PKS I - - - 93/96 acyltransferase domain-containing protein, Amycolatopsis albispora (WP_113696550.1); QmnA3 1292 PKS I - - - 86/90 QmnE 412 - serine hydrolase, Sorangium cellulosum (KYF55935.1); 58/71 - - - QmnF 396 - cysteine desulfurase-like protein, Amycolatopsis albispora (WP_113696547.1); 89/92 - - - QmnRg 255 - activator protein, Amycolatopsis albispora (WP_113696546.1); 98/98 - - - 1 QmnG 533 PQQ-dependent dehydrogenase hypothetical protein, Amycolatopsis albispora (WP_113696544.1); 93/95 - - - QmnH 376 Diels-Alderase hypothetical protein, Amycolatopsis albispora (WP_113696543.1); 94/97 AbyU AbsU AbmU HlyD family efflux transporter periplasmic adaptor subunit, Amycolatopsis albispora QmnI 348 - - - - (WP_113696542.1); 88/93 QmnJ 161 - hypothetical protein, Amycolatopsis albispora (WP_113696541.1); 88/93 - - - QmnRs1 392 transporter ABC transporter permease, Amycolatopsis albispora (WP_113696540.1); 97/98 - - - QmnRs2 227 transporter ABC transporter ATP-binding protein, Amycolatopsis albispora (WP_113696539.1); 96/99 - - - HlyD family efflux transporter periplasmic adaptor subunit, Amycolatopsis albispora QmnK 352 - - - - (WP_113696538.1); 96/97 QmnL 152 - hypothetical protein, Amycolatopsis albispora (WP_113696537.1); 88/90 - - - QmnM 219 - hypothetical protein, Streptomyces rimosus (WP_030595123.1); 58/69 - - - QmnN 130 hypothetical protein, Streptomyces rimosus (WP_030674267.1); 65/74 - - - QmnRg 449 regulator HAMP domain-containing protein, Amycolatopsis albispora (WP_113696536.1); 90/94 - - - 2 QmnRg 222 regulator response regulator transcription factor, Amycolatopsis albispora (WP_113698159.1); 99/99 - - - 3 3-oxoacyl-ACP synthase III family protein, Amycolatopsis albispora (WP_113696535.1); QmnD5 343 3-oxoacyl-ACP synthase III (KS) - - - 95/98 QmnD1 613 glyceryltransferase/phosphatase HAD-IIIC family phosphatase, Amycolatopsis albispora (WP_113696534.1); 91/94 - - - QmnD2 71 ACP acyl carrier protein, Amycolatopsis albispora (WP_113696533.1); 94/97 - - -

101 2-oxoacid dehydrogenase, QmnD3 281 acyltransferase, Amycolatopsis albispora (WP_113696532.1); 83/87 - - - acyltransferase QmnO 403 cytochrome p450 cytochrome P450, Amycolatopsis albispora (WP_113696531.1); 95/97 - - - QmnRg 935 regulator LuxR family transcriptional regulator, Amycolatopsis albispora (WP_113698158.1); 95/96 - - - 4 QmnRg 821 regulator transcriptional regulator, Amycolatopsis albispora (WP_113696530.1); 90/92 - - - 5

102 Table S61. Predicted functions of ORFs in potential BGC from Pantoea sp. A4 (NZ_ALXE01000017).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog B880_RS010364 DMT family transporter, Enterobacteriaceae bacterium strain FGI 57 163 DMT family transporter - - - 0 (WP_015965015.1); 94/97 B880_RS010364 458 hypothetical protein MmgE/PrpD family protei, Serratia sp. P2ACOL2 (WP_122079351.1); 74/83 - - - 5 B880_RS010365 DHA2 family efflux MFS transporter 503 Multidrug resistance protein stp, Serratia marcescens (SAY43176.1); 72/83 - - - 0 permease subunit B880_RS010365 TetR/AcrR family transcriptional 212 TetR family transcriptional regulator, Yersinia intermedia (CQD48424.1); 71/81 - - - 5 regulator B880_RS010366 ABC transporter substrate-binding ABC transporter substrate-binding protein, Serratia sp. P2ACOL2 385 - - - 0 protein (WP_122079353.1); 64/79 B880_RS010366 TonB-dependent siderophore TonB-dependent siderophore receptor, Serratia sp. P2ACOL2 715 - - - 5 receptor (WP_122079354.1); 69/84 B880_RS010367 73 hypothetical protein hypothetical protein, Yersinia intermedia (WP_050881852.1); 59/77 - - - 0 B880_RS010367 535 hypothetical protein RosA, Erwinia rhapontici (AMB18979.1); 70/80 - - - 5 B880_RS010368 242 thioesterase thioesterase, Erwinia persicina (WP_118665708.1); 58/72 - - - 0 B880_RS010368 pyridoxal-phosphate dependent pyridoxal-phosphate dependent enzyme, Erwinia rhapontici 342 - - - 5 enzyme (WP_133843159.1); 85/91 B880_RS010369 184 Diels-Alderase RosD, Erwinia rhapontici (AMB18976.1); 78/89 AbyU AbsU AbmU 0 B880_RS010369 391 FAD-dependent oxidoreductase - - - - 5 B880_RS010370 acyltransferase domain-containing protein, Erwinia persicina 961 PKS I - - - 0 (WP_062742714.1); 69/81 B880_RS010370 344 Glu/Leu/Phe/Val dehydrogenase RosG, Erwinia rhapontici (AMB18973.1); 78/87 - - - 5 B880_RS010371 366 hypothetical protein hypothetical protein, Serratia sp. P2ACOL2 (WP_122079360.1); 59/71 - - - 0 B880_RS010371 131 hypothetical protein DNA-binding protein, Pantoea rwandensis (WP_084932292.1); 61/75 - - - 5 B880_RS010372 289 aldo/keto reductase aldo/keto reductase, Escherichia marmotae (PGF73638.1); 85/93 - - - 0 B880_RS010372 439 FAD-dependent oxidoreductase FAD-binding oxidoreductase, Pantoea wallisii (WP_128601728.1); 81/93 - - - 5 B880_RS010373 443 MFS transporter MFS transporter, Pseudomonas reidholzensis (WP_119143972.1); 77/89 - - - 0 B880_RS010373 transporter substrate-binding transporter substrate-binding domain-containing protein, Pantoea sp. YU22 277 - - - 5 domain-containing protein (WP_126689428.1); 81/88

103 104 Table S62. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces paucisporeus CGMCC 4.2025 (NZ_FRBI01000008).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) type I polyketide synthase, Micromonospora sp. GMKU326 BUE44_RS14365 - PKS I PKS I PKS I PKS I (BAQ25511.1); 58/67 MFS transporter, Streptomyces griseorubiginosus (WP_123763219.1); BUE44_RS14370 505 MFS transporter AbyD AbsD AbmD 58/74 cytochrome P450, Amycolatopsis sp. CA-126428 (WP_103341807.1); BUE44_RS14375 390 cytochrome P450 AbyX/AbyV AbsV/AbsX AbmV 54/71 BUE44_RS14380 102 ferredoxin ferredoxin, Lentzea kentuckyensis (WP_086665861.1); 63/77 - AbsG1/AbsG2 AbmG cytochrome P450, Amycolatopsis sp. CA-126428 (WP_103341807.1); BUE44_RS14385 388 cytochrome P450 AbyX/AbyV AbsV/AbsX AbmV 54/69 SDR family NAD(P)-dependent SDR family oxidoreductase, Streptoalloteichus hindustanus BUE44_RS14390 239 - - - oxidoreductase (WP_073489819.1); 53/66 FAD/NAD(P)-binding protein, Streptomyces cattleya BUE44_RS14395 680 FAD/NAD(P)-binding protein - - - (WP_014141705.1); 49/59 acyltransferase, Streptomyces sp. WAC 06738 (WP_125933459.1); BUE44_RS14400 238 hypothetical protein AbyA4 AbsA4 AbmA4 67/78 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. 2131.1 BUE44_RS14405 353 AbyA1 AbsA1 AbmA1 family protein (WP_093710000.1); 66/77 hypothetical protein, Streptomyces griseorubiginosus BUE44_RS14410 188 Diels-Alderase AbyU AbsU AbmU (WP_123763217.1); 44/58 BUE44_RS14415 75 acyl carrier protein acyl carrier protein, Umezawaea tangerina (WP_106194434.1); 68/80 AbyA3 AbsA3 AbmA3 AfsR/SARP family transcriptional SARP family transcriptional regulator, Streptomyces sp. E14 BUE44_RS14420 258 AbyI/AbyR - AbmI regulator (WP_009191683.1); 51/64 SAM-dependent SAM-dependent methyltransferase, Nonomuraea sp. KC201 BUE44_RS14425 273 - - - methyltransferase (WP_132330820.1); 53/65 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Streptomyces hoynatensis BUE44_RS14430 202 - AbsC2 - regulator (WP_120678650.1); 50/60 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces formicae BUE44_RS14435 356 AbyE AbsE AbmE1 oxidoreductase (WP_098241239.1); 59/73 LuxR family transcriptional LuxR family transcriptional regulator, Streptomyces sp. 57 BUE44_RS14440 950 AbyH - AbmH regulator (WP_121408891.1); 41/53 AfsR/SARP family transcriptional SARP family transcriptional regulator, Streptomyces sp. E14 BUE44_RS14445 263 AbyI/AbyR - AbmI regulator (WP_009191683.1); 62/77 cytochrome P450, Streptomyces griseoruber (WP_055634261.1); BUE44_RS14450 403 cytochrome P450 AbyX/AbyV AbsV/AbsX AbmV 55/71 alpha/beta fold hydrolase, Streptomyces sp. MUSC 1 BUE44_RS14455 277 alpha/beta fold hydrolase - - - (WP_071384385.1); 65/77

105 Table S63. Predicted functions of ORFs in potential chlorothricin BGC from Actinomadura pelletieri DSM 43383 (NZ_RBWU01000008).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog BZB76_RS31630 476 NDP-hexose 2,3-dehydratase ChlC3, Streptomyces antibioticus (AAZ77682.1); 65/73 - - - BZB76_RS31635 79 hypothetical protein hypothetical protein, Actinomadura sp. LMG 30035 (WP_131741591.1); 48/62 - - - BZB76_RS31640 262 thioesterase thioesterase, Streptomyces armeniacus (AXK32421.1); 59/69 - - - AfsR/SARP family BZB76_RS31645 266 activator protein, Streptomyces armeniacus (AXK32420.1); 71/79 - - - transcriptional regulator BZB76_RS31650 754 MMPL family transporter MMPL family transporter, Aeromicrobium sp. Root236 (WP_056402437.1); 56/72 - - - BZB76_RS31655 368 alpha/beta hydrolase alpha/beta hydrolase, Actinomadura chibensis (WP_067904591.1); 67/77 - - - BZB76_RS31660 266 acyltransferase acyltransferase, Actinocrispum wychmicini (WP_132116034.1); 71/81 - - - BZB76_RS31665 74 acyl carrier protein acyl carrier protein, Actinocrispum wychmicini (WP_132116036.1); 60/73 - - - BZB76_RS31670 636 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Micromonospora sp. RP3T (WP_107154962.1); 65/76 - - - 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Actinocrispum wychmicini BZB76_RS31675 343 - - - family protein (WP_132116040.1); 76/87 BZB76_RS31680 501 hypothetical protein hypothetical protein DVA86_06945, Streptomyces armeniacus (AXK32428.1); 61/71 - - - acyltransferase domain- acyltransferase domain-containing protein, Streptomyces armeniacus (AXK32430.1); BZB76_RS31685 1507 - - - containing protein 57/67 BZB76_RS31690 3910 PKS I type I polyketide synthase, Micromonospora sp. Rc5 (WP_077939335.1); 61/71 - - - SDR family NAD(P)-dependent oxidoreductase, partial, Candidatus Streptomyces BZB76_RS31695 589 PKS I - - - philanthi (WP_114025722.1); 53/67 BZB76_RS31700 377 PKS I type I polyketide synthase, Streptomyces eurocidicus (WP_102919106.1); 48/61 - - - BZB76_RS31705 777 PKS I ChlA4, Streptomyces antibioticus (AAZ77697.1); 65/77 - - - SDR family NAD(P)-dependent oxidoreductase, Streptomyces alboflavus BZB76_RS31710 5163 PKS I - - - (WP_125262906.1); 53/65 SDR family NAD(P)-dependent oxidoreductase, Actinocrispum wychmicini BZB76_RS31715 1542 PKS I - - - (WP_132116050.1); 57/67 SDR family NAD(P)-dependent oxidoreductase, Actinocrispum wychmicini BZB76_RS31720 263 PKS I - - - (WP_132116052.1); 69/78 BZB76_RS31725 112 PKS I type I polyketide synthase, Actinomadura macra (WP_067456430.1); 62/69 - - - BZB76_RS31730 316 PKS I polyketide synthase subunit, partial, Streptomyces sp. RSD-27 (KIF04675.1); 68/76 - - - Acyl transferase domain-containing protein, partial, Actinoplanes regularis BZB76_RS31735 67 PKS I - - - (SNT04067.1); 70/79 BZB76_RS31740 881 PKS I type I polyketide synthase, Streptomyces hygroscopicus (WP_066029228.1); 64/75 - - - SDR family NAD(P)-dependent oxidoreductase, Actinomadura sp. LHW52907 BZB76_RS31745 967 PKS I - - - (WP_117405125.1); 64/73

106 SDR family NAD(P)-dependent oxidoreductase, Actinomadura sp. LHW52907 BZB76_RS31750 375 PKS I - - - (WP_117405125.1); 55/66 type I polyketide synthase, partial, Streptomyces sp. CNQ766 (WP_018840958.1); BZB76_RS31755 336 PKS I - - - 61/69 KR domain-containing protein, partial, Streptomyces sp. AZ1-7 (WP_120745073.1); BZB76_RS31760 251 PKS I - - - 46/55 Acyl transferase domain-containing protein, Streptomyces sp. 2314.4 (SEE65811.1); BZB76_RS31765 1835 PKS I - - - 55/66 glucose-1-phosphate BZB76_RS31770 355 ChlC1, Streptomyces antibioticus (AAZ77690.1); 64/75 - - - thymidylyltransferase 3-hydroxyacyl-CoA 3-hydroxyacyl-CoA dehydrogenase family protein, Streptomyces sioyaensis BZB76_RS31775 579 - - - dehydrogenase family protein (WP_129246466.1); 63/73 beta-ketoacyl-ACP synthase BZB76_RS31780 347 ketoacyl-ACP synthase III, Streptomyces sp. C (WP_007269134.1); 70/80 - - - 3 crotonyl-CoA crotonyl-CoA carboxylase/reductase, Streptoalloteichus hindustanus (SHG03036.1); BZB76_RS31785 444 - - - carboxylase/reductase 81/91 BZB76_RS31790 89 acyl carrier protein ChlB2, Streptomyces antibioticus (AAZ77675.1); 51/67 - - - NAD(P)/FAD-dependent BZB76_RS31795 453 FAD-dependent oxidoreductase, Actinocrispum wychmicini (WP_132116064.1); 79/88 - - - oxidoreductase acyltransferase domain- acyltransferase domain-containing protein, Streptomyces armeniacus (AXK33367.1); BZB76_RS31800 1785 - - - containing protein 66/74 BZB76_RS31805 347 3-oxoacyl-ACP synthase 3-oxoacyl-ACP synthase, Actinocrispum wychmicini (WP_132116060.1); 74/84 - - - BZB76_RS31810 67 hypothetical protein - - - - BZB76_RS31815 186 Diels-Alderase hypothetical protein, Actinocrispum wychmicini (WP_132116074.1); 45/57 AbyU AbsU AbmU DegT/DnrJ/EryC1/StrS family DegT/DnrJ/EryC1/StrS family aminotransferase, Streptomyces exfoliatus BZB76_RS31820 384 - - - aminotransferase (WP_030554129.1); 69/81 BZB76_RS31825 348 3-oxoacyl-ACP synthase 3-oxoacyl-ACP synthase, Amycolatopsis palatopharyngis (WP_116051422.1); 51/69 - - - DUF1205 domain-containing DUF1205 domain-containing protein, Actinocrispum wychmicini (WP_132116056.1); BZB76_RS31830 406 - - - protein 48/65 BZB76_RS31835 405 cytochrome P450 cytochrome P450, Streptomyces sp. LHW50302 (WP_114017402.1); 65/75 - - -

107 Table S64. Predicted functions of ORFs in potential BGC from Candidatus Streptomyces philanthi (NZ_QOIN01000036).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog polyketide synthase, partial, Streptomyces sp. LHW50302 (RCG16060.1); DTL70_RS08705 - PKS I - - - 90/93 DTL70_RS08710 201 Diels-Alderase hypothetical protein, Streptomyces sp. LHW50302 (WP_114017401.1); 98/99 AbyU AbsU AbmU DTL70_RS08715 403 cytochrome P450 cytochrome P450, Streptomyces sp. LHW50302 (WP_114017402.1); 99/99 - - - DTL70_RS08720 253 methyltransferase methyltransferase, Streptomyces sp. LHW50302 (WP_114017403.1); 98/99 - - - 3-oxoacyl-ACP synthase, Streptomyces sp. LHW50302 (WP_114017404.1); DTL70_RS08725 347 3-oxoacyl-ACP synthase - - - 99/99 type I polyketide synthase, Streptomyces sp. LHW50302 (WP_114017405.1); DTL70_RS08730 1817 PKS I - - - 94/95 dTDP-glucose 4,6-dehydratase, Streptomyces sp. LHW50302 DTL70_RS08735 323 dTDP-glucose 4,6-dehydratase - - - (WP_114017406.1); 98/99 helix-turn-helix transcriptional helix-turn-helix transcriptional regulator, Streptomyces sp. LHW50302 DTL70_RS08740 974 - - - regulator (WP_114017407.1); 95/96 DUF2075 domain-containing protein, Streptomyces sp. LHW50302 DTL70_RS08745 776 DUF2075 domain-containing protein - - - (WP_114017408.1); 97/98 dTDP-4-keto-6-deoxy-D-glucose dTDP-4-keto-6-deoxy-D-glucose epimerase, Streptomyces sp. LHW50302 DTL70_RS08750 202 - - - epimerase (WP_114017409.1); 99/99 DTL70_RS08755 307 putative sugar O-methyltransferase NanM, Streptomyces nanchangensis (AAP42862.1); 61/77 - - - DUF1205 domain-containing protein, Streptomyces sp. LHW50302 DTL70_RS08760 403 DUF1205 domain-containing protein - - - (WP_114017411.1); 97/97 class I SAM-dependent class I SAM-dependent methyltransferase, Streptomyces sp. LHW50302 DTL70_RS08765 265 - - - methyltransferase (WP_114017412.1); 98/100 class I SAM-dependent class I SAM-dependent methyltransferase, Streptomyces sp. LHW50302 DTL70_RS08770 415 - - - methyltransferase (WP_114017413.1); 99/99

108 Table S65. Predicted functions of ORFs in potential BGC from Streptomyces rimosus subsp. rimosus NRRL B-16073 (NZ_JNWX01000004).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog NH06_RS0106110 533 amidase amidase, Streptomyces sp. NRRL WC-3701 (KOT47522.1); 99/99 - - - SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. WAC 06783 NH06_RS0106115 283 oxidoreductase - - - (WP_125520864.1); 98/98 helix-turn-helix domain-containing protein, Streptomyces sp. WAC 06783 NH06_RS0106120 290 transcriptional regulator - - - (WP_125520863.1); 100/100 DegT/DnrJ/EryC1/StrS family DegT/DnrJ/EryC1/StrS family aminotransferase, Streptomyces albus NH06_RS0106125 421 - - - aminotransferase (WP_060732997.1); 99/99 streptomycin biosynthesis streptomycin biosynthesis protein, Streptomyces sp. WAC 06783 NH06_RS0106130 335 - - - protein (WP_125520938.1); 99/99 NH06_RS0106135 79 acyl carrier protein acyl carrier protein, Streptomyces sp. WAC 06783 (RSO08986.1); 99/100 - - - (2,3-dihydroxybenzoyl)adenylate 2,3-dihydroxybenzoate--AMP ligase, Kitasatospora aureofaciens (KOG75552.1); NH06_RS0106140 570 - - - synthase 99/99 alpha/beta fold hydrolase, Streptomyces sp. WAC 06725 (WP_125532514.1); NH06_RS0106145 255 thioesterase - - - 99/99 FAD-dependent oxidoreductase, Streptomyces sp. WAC 06725 NH06_RS0106150 402 FAD-dependent oxidoreductase - - - (WP_125532515.1); 99/99 acyltransferase domain-containing protein, Streptomyces sp. WAC 06725 NH06_RS0106155 979 PKS I - - - (WP_125532516.1); 99/98 CGNR zinc finger domain- CGNR zinc finger domain-containing protein, Streptomyces sp. WAC 06725 NH06_RS0106160 173 - - - containing protein (RSO35445.1); 99/99 NH06_RS0106165 448 MFS transporter MFS transporter, Streptomyces sp. WAC 06783 (WP_125520937.1); 99/99 - - - hypothetical protein DMH18_19415, Streptomyces sp. WAC 06783 (RSO08979.1); NH06_RS0106170 174 Diels-Alderase AbyU AbsU AbmU 99/100 NH06_RS0106175 433 MFS transporter MFS transporter, Kitasatospora aureofaciens (KOG75546.1); 99/99 - - - NH06_RS0106180 435 hypothetical protein hypothetical protein, Streptomyces sp. NRRL F-5755 (WP_053700239.1); 99/99 - - - UDP-N-acetylmuramate UDP-N-acetylmuramate dehydrogenase, Streptomyces sp. NRRL F-5755 NH06_RS0106185 367 - - - dehydrogenase (WP_053700238.1); 99/98 NH06_RS0106190 332 iron ABC transporter iron ABC transporter, Streptomyces sp. WAC 06783 (RSO09087.1); 99/99 - - - iron ABC transporter permease, Kitasatospora aureofaciens (KOG75678.1); NH06_RS0106195 376 iron ABC transporter permease - - - 99/100 ABC transporter substrate-binding protein, Streptomyces sp. WAC 06783 NH06_RS0106200 331 iron siderophore-binding protein - - - (WP_125520857.1); 99/99

109 Table S66. Predicted functions of ORFs in abyssomicin BGC from Streptomyces sp. Amel2xE9 (NZ_KB912999 and NZ_KB912981).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog AfsR/SARP family transcriptional SARP family transcriptional regulator, Streptomyces sp. E14 B065_RS0132280 257 AbyI/AbyR - AbmI regulator (WP_009191683.1); 99/99 B065_RS0132285 945 LuxR family transcriptional regulator transcription regulator, Streptomyces sp. LC-6-2 (ARE67835.1); 99/99 AbyH - AbmH B065_RS0132290 476 MFS transporter MFS transporter, Streptomyces sp. E14 (WP_043261567.1); 99/99 AbyD AbsD AbmD TetR/AcrR family transcriptional B065_RS0132295 196 AbsC2, Streptomyces sp. LC-6-2 (ARE67837.1); 99/100 - AbsC2 - regulator B065_RS0132300 128 Diels-Alderase conserved hypothetical protein, Streptomyces sp. E14 (EFF94138.1); 99/99 AbyU AbsU AbmU B065_RS0132305 344 aldo/keto reductase aldo/keto reductase, Streptomyces sp. E14 (WP_050790870.1); 99/99 - AbsJ AbmJ B065_RS0132310 64 ferredoxin AbsG2, Streptomyces sp. LC-6-2 (ARE67840.1); 100;100 - AbsG2 - B065_RS0132315 403 cytochrome P450 cytochrome P450, Streptomyces sp. E14 (WP_009191676.1); 99/99 AbyX AbsX - B065_RS0132320 387 acyltransferase acyltransferase, Streptomyces sp. E14 (WP_009191675.1); 99/99 - AbsI - B065_RS0132325 68 ferredoxin AbsG1, Streptomyces sp. LC-6-2 (ARE67843.1); 100/100 - AbsG1 AbmG B065_RS0132330 397 cytochrome P450 AbsV, Streptomyces sp. LC-6-2 (ARE67844.1); 99/100 AbyV AbsV AbmV B065_RS0132335 555 ABC transporter ATP-binding protein AbsF4, Streptomyces sp. LC-6-2 (ARE67845.1); 98/98 AbyF4 AbsF4 AbmF4 B065_RS0132340 249 ABC transporter permease AbsF3, Streptomyces sp. LC-6-2 (ARE67846.1); 99/99 AbyF3 AbsF3 AbmF3 B065_RS0132345 333 ABC transporter permease AbsF2, Streptomyces sp. LC-6-2 (ARE67847.1); 99/99 AbyF2 AbsF2 AbmF2 ABC transporter substrate-binding B065_RS0132350 554 AbsF1, Streptomyces sp. LC-6-2 (ARE67848.1); 99/99 AbyF1 AbsF1 AbmF1 protein LLM class flavin-dependent B065_RS0132355 328 AbsE, Streptomyces sp. LC-6-2 (ARE67849.1); 99/99 AbyE AbsE AbmE1 oxidoreductase B065_RS0132360 649 HAD-IIIC family phosphatase AbsA2, Streptomyces sp. LC-6-2 (ARE67850.1); 99/99 AbyA2 AbsA2 AbmA2 B065_RS0132365 1049 PKS I AbsB3, Streptomyces sp. LC-6-2 (ARE67851.1); 98/98 AbyB3 AbsB3 AbmB3 B065_RS0132370 3662 PKS I AbsB2, Streptomyces sp. LC-6-2 (ARE67852.1); 96/96 AbyB2 AbsB2 AbmB2 B065_RS39245 - PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 97/97 AbyB1 AbsB1 AbmB1 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// B065_RS38160 - PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 98/98 AbyB1 AbsB1 AbmB1 B065_RS41620 69 hypothetical protein - - - - B065_RS0128140 275 thioesterase thioesterase, Streptomyces sp. E14 (WP_009191660.1); 99/99 AbyT AbsN AbmT B065_RS0128145 381 alpha/beta hydrolase AbsA5, Streptomyces sp. LC-6-2 (ARE67854.1); 98/98 AbyA5 AbsA5 AbmA5

110 B065_RS0128150 251 acyltransferase AbsA4, Streptomyces sp. LC-6-2 (ARE67855.1); 100/100 AbyA4 AbsA4 AbmA4 B065_RS0128155 77 acyl carrier protein AbsA3, Streptomyces sp. LC-6-2 (ARE67856.1); 97/97 AbyA3 AbsA3 AbmA3 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. E14 B065_RS0128160 351 AbyA1 AbsA1 AbmA1 protein (WP_063821841.1); 99/99 flavin reductase domain-containing protein, Streptomyces sp. E14 B065_RS0128165 190 flavin reductase family protein AbyZ AbsH1 AbmZ (EFF94116.1); 98/97 B065_RS0128170 117 oxidoreductase AbsH2, Streptomyces sp. LC-6-2 (ARE67859.1); 100/100 - AbsH2 -

111 Table S67. Predicted functions of ORFs in abyssomicin BGC from Streptomyces sp. e14 (NZ_GG753626.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog type IV secretion protein Rhs, Streptomyces sp. Amel2xE9 (WP_019984805.1); SSTG_RS22930 1190 RHS repeat protein AbyK - - 99/99 SSTG_RS22935 191 short-chain dehydrogenase short-chain dehydrogenase, Rhodococcus sp. 06-156-4C (OZD08776.1); 80/86 - - - SSTG_RS22940 301 alpha/beta fold hydrolase AbsP, Streptomyces sp. LC-6-2 (ARE67863.1); 99/99 - AbsP - histidine phosphatase family SSTG_RS22945 209 AbsK, Streptomyces sp. LC-6-2 (ARE67862.1); 97/98 - AbsK - protein TetR family transcriptional SSTG_RS22950 232 AbsC1, Streptomyces sp. LC-6-2 (ARE67861.1); 99/100 - AbsC1 - regulator SSTG_RS22955 387 oxidoreductase AbsH3, Streptomyces sp. LC-6-2 (ARE67860.1); 98/98 - AbsH3 - SSTG_RS22960 117 oxidoreductase AbsH2, Streptomyces sp. LC-6-2 (ARE67859.1); 100/100 AbyZ AbsH1 AbmZ SSTG_RS22965 163 flavin reductase family protein AbsH1, Streptomyces sp. LC-6-2 (ARE67858.1); 99/100 - AbsH2 - 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. Amel2xE9 SSTG_RS22970 351 AbyA1 AbsA1 AbmA1 protein (WP_019984792.1); 99/99 SSTG_RS22975 77 acyl carrier protein acyl carrier protein, Streptomyces sp. Amel2xE9 (WP_019984791.1); 97/97 AbyA3 AbsA3 AbmA3 SSTG_RS22980 251 acyltransferase AbsA4, Streptomyces sp. LC-6-2 (ARE67855.1); 100/100 AbyA4 AbsA4 AbmA4 SSTG_RS22985 89 alpha/beta hydrolase AbsA5, Streptomyces sp. LC-6-2 (ARE67854.1); 98/98 AbyA5 AbsA5 AbmA5 SSTG_RS22990 275 thioesterase AbsN, Streptomyces sp. LC-6-2 (ARE67865.1); 99/99 AbyT AbsN AbmT SSTG_RS34725 87 hypothetical protein - - - - SSTG_RS33420 561 PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 96/96 PKS I PKS I PKS I SSTG_RS34730 - PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 99/99 PKS I PKS I PKS I SSTG_RS34735 - PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 91/92 PKS I PKS I PKS I SSTG_RS34740 - PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 98/99 PKS I PKS I PKS I SSTG_RS34745 - PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 98/98 PKS I PKS I PKS I SSTG_RS23005 - PKS I - PKS I PKS I PKS I SSTG_RS23010 - PKS I - PKS I PKS I PKS I SSTG_RS33430 - PKS I - PKS I PKS I PKS I SSTG_RS23020 - PKS I AbsB2, Streptomyces sp. LC-6-2 (ARE67852.1); 100/100 PKS I PKS I PKS I SSTG_RS23025 - PKS I AbsB2, Streptomyces sp. LC-6-2 (ARE67852.1); 96/96 PKS I PKS I PKS I SSTG_RS23030 - PKS I - PKS I PKS I PKS I

112 SSTG_RS23035 - PKS I - PKS I PKS I PKS I SSTG_RS23040 - PKS I AbsB3, Streptomyces sp. LC-6-2 (ARE67851.1); 99/100 PKS I PKS I PKS I SSTG_RS23045 - PKS I - PKS I PKS I PKS I methoxymalonyl-ACP SSTG_RS23050 588 AbsA2, Streptomyces sp. LC-6-2 (ARE67850.1); 98/97 AbyA2 AbsA2 AbmA2 biosynthesis protein FkbH SSTG_RS23055 353 cytochrome P450 AbsV, Streptomyces sp. LC-6-2 (ARE67844.1); 100/100 AbyV AbsV AbmV SSTG_RS23060 68 ferredoxin AbsG1, Streptomyces sp. LC-6-2 (ARE67843.1); 100/100 - AbsG1 AbmG SSTG_RS23065 387 acyltransferase acyltransferase, Streptomyces sp. Amel2xE9 (WP_019985553.1); 99/99 - AbsI - SSTG_RS23070 403 cytochrome P450 cytochrome P450, Streptomyces sp. Amel2xE9 (WP_019985552.1); 99/99 AbyX AbsX - SSTG_RS23075 64 ferredoxin AbsG2, Streptomyces sp. LC-6-2 (ARE67840.1); 100/100 - AbsG2 - SSTG_RS23080 344 aldo/keto reductase AbsJ, Streptomyces sp. LC-6-2 (ARE67839.1); 100/100 - AbsJ AbmJ SSTG_RS23085 171 Diels-Alderase AbsU, Streptomyces sp. LC-6-2 (ARE67838.1); 100/100 AbyU AbsU AbmU TetR/AcrR family transcriptional SSTG_RS23090 196 AbsC2, Streptomyces sp. LC-6-2 (ARE67837.1); 99/99 - AbsC2 - regulato SSTG_RS23095 476 MFS transporter AbsD, Streptomyces sp. LC-6-2 (ARE67836.1); 100/100 AbyD AbsD AbmD LuxR family transcriptional regulator, Streptomyces sp. Amel2xE9 SSTG_RS23100 688 ATP-binding protein AbyH - AbmH (WP_019985546.1); 99/99 AfsR/SARP family transcriptional SARP family transcriptional regulator, Streptomyces sp. Amel2xE9 SSTG_RS23105 257 AbyI - AbmI regulator (WP_019985545.1); 99/99

113 Table S68. Predicted functions of ORFs in abyssomicin BGC from Streptomyces fragilis NBRC 12862 (NZ_BEVZ01000002.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog Sfr03f_RS07880 859 RHS repeat protein hypothetical protein ACZ91_47855, Streptomyces regensis (KMS84453.1); 76/81 AbyK - - Sfr03f_RS07885 134 Diels-Alderase YD repeat-containing protein, Streptomyces regensis (KMS84434.1); 95/95 AbyU AbsU AbmU 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces regalis Sfr03f_RS07890 344 AbyA1 AbsA1 AbmA1 family protein (WP_062712132.1); 87/93 Sfr03f_RS07895 626 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Streptomyces (WP_078865191.1); 84/88 AbyA2 AbsA2 AbmA2 Sfr03f_RS07900 75 acyl carrier protein acyl carrier protein, Streptomyces sp. NRRL WC-3725 (WP_031029037.1); 92/95 AbyA3 AbsA3 AbmA3 Sfr03f_RS07905 258 acyltransferase Acyltransferase, Streptomyces (WP_051818896.1); 84/90 AbyA4 AbsA4 AbmA4 Sfr03f_RS07910 360 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces (WP_030991268.1); 88/92 AbyA5 AbsA5 AbmA5 Sfr03f_RS07915 166 flavin reductase flavin oxidoreductase, Streptomyces regensis (KMS84438.1); 84/87 AbyZ AbsH1 AbmZ TetR/AcrR family transcriptional Sfr03f_RS07920 229 TetR/AcrR family transcriptional regulator, Streptomyces (WP_031100136.1); 90/95 AbyC - AbmC regulator DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Streptomyces sp. NRRL Sfr03f_RS07925 461 AbyD AbsD AbmD transporter permease subunit WC-3744 (WP_030991264.1); 90/93 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces regalis Sfr03f_RS07930 345 AbyE AbsE AbmE1 oxidoreductase (WP_062712142.1); 87/91 ABC transporter substrate- ABC transporter substrate-binding protein, Streptomyces sp. NRRL WC-3744 Sfr03f_RS07935 546 AbyF1 AbsF1 AbmF1 binding protein (WP_030991261.1); 80/86 Sfr03f_RS07940 315 ABC transporter permease ABC transporter permease, Streptomyces regensis (KMS84443.1); 84/90 AbyF2 AbsF2 AbmF2 Sfr03f_RS07945 297 ABC transporter permease ABC transporter permease, Streptomyces regalis (WP_062712151.1); 80/86 AbyF3 AbsF3 AbmF3 ABC transporter ATP-binding Sfr03f_RS07950 543 ABC transporter ATP-binding protein, Streptomyces (WP_031029029.1); 84/87 AbyF4 AbsF4 AbmF4 protein Sfr03f_RS07955 434 acyltransferase Acyltransferase, Streptomyces regalis (WP_062712154.1); 79/85 - AbsI - Sfr03f_RS07960 406 cytochrome P450 cytochrome P450, Streptomyces (WP_030654493.1); 92/95 AbyV/AbyX AbsV/AbsX AbmV Sfr03f_RS07965 64 ferredoxin Ferredoxin, Streptomyces (WP_030654496.1); 92/95 - AbsG1 AbmG Sfr03f_RS07970 307 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces (WP_030654499.1); 90/92 - - - Sfr03f_RS07975 6216 PKS I type I polyketide synthase, Streptomyces sp. 2131.1 (WP_093709985.1); 64/72 AbyB1 AbsB1 AbmB1 Sfr03f_RS07980 3846 PKS I type I polyketide synthase, Streptomyces sp. 2131.1 (WP_093709984.1); 68/76 AbyB2 AbsB2 AbmB2 Sfr03f_RS07985 960 PKS I type I polyketide synthase, Streptomyces sp. 2131.1 (WP_093709983.1); 73/80 type I polyketide synthase, Streptomyces sp. NRRL WC-3725 (WP_043195775.1); AbyB3 AbsB3 AbmB3 Sfr03f_RS07990 77 PKS I 89/97 Sfr03f_RS07995 393 cytochrome P450 cytochrome P450, Streptomyces (WP_031101897.1); 85/90 AbyX/AbyV AbsV/AbsX AbmV Table S69. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces incarnatus NRRL 8089 (CP011497).

114 Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog LLM class flavin-dependent oxidoreductase, Streptomyces sp. Amel2xE9 ABB07_01775 339 luciferase - - AbmE2 (WP_106962144.1); 91/94 ABB07_01780 399 cytochrome P450 cytochrome P450, Streptomyces sp. NRRL WC-3742 (WP_031075102.1); 72/81 AbyV AbsV AbmV ABB07_01785 71 hypothetical protein ferredoxin, Streptomyces sp. KE1 (WP_047140955.1); 55/71 AbyW - - ABB07_01790 347 luciferase LLM class flavin-dependent oxidoreductase, Frankia alni (WP_011601492.1); 57/69 AbyE AbsE AbmE1 ABB07_01795 497 MFS transporter MFS transporter, Streptomyces sp. Amel2xE9 (WP_019985547.1); 64/76 AbyD AbsD AbmD TetR family transcriptional TetR/AcrR family transcriptional regulator, Microbispora rosea (WP_076442332.1); ABB07_01800 201 - AbsC2 - regulator 775/82 nitrilotriacetate LLM class flavin-dependent oxidoreductase, Frankia symbiont of Coriaria ruscifolia ABB07_01805 447 - - - monooxygenase (WP_131785890.1); 78/87 ABB07_01810 514 hypothetical protein hypothetical protein, Frankia sp. BMG5.30 (WP_047223156.1); 55/72 AbyF1 AbsF1 AbmF1 ABB07_01815 270 hypothetical protein ABC transporter ATP-binding protein, Frankia sp. BMG5.30 (WP_083731087.1); 62/74 AbyF4 AbsF4 AbmF4 ATP-binding cassette domain-containing protein, Frankia symbiont of Datisca glomerata ABB07_01820 269 hypothetical protein AbyF4 AbsF4 AbmF4 (WP_013873338.1); 65/75 ABC transporter permease subunit, Frankia symbiont of Coriaria nepalensis ABB07_01825 289 hypothetical protein AbyF3 AbsF3 AbmF3 (WP_131772430.1); 57/71 ABC-type transporter, integral membrane subunit, Frankia symbiont of Datisca ABB07_01830 342 ABC transporter permease AbyF2 AbsF2 AbmF2 glomerata (AEH09395.1); 62/75 ABB07_01835 332 aldo/keto reductase aldo/keto reductase, Streptacidiphilus sp. DSM 106435 (WP_111492774.1); 76/84 - AbsJ AbmJ acyltransferase domain-containing protein, Streptacidiphilus sp. DSM 106435 ABB07_01840 1069 hypothetical protein AbyB3 AbsB3 AbmB3 (WP_111490411.1); 60/68 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. NRRL WC-3742 ABB07_01855 343 3-oxoacyl-ACP synthase AbyA1 AbsA1 AbmA1 (WP_031075097.1); 71/81 ABB07_01860 135 Diels-Alderase hypothetical protein, Streptomyces sp. CB03911 (WP_073928710.1); 71/87 AbyU AbsU AbmU ABB07_01865 6174 PKS I type I polyketide synthase, Streptomyces fragilis (WP_108952947.1); 55/63 AbyB1 AbsB1 AbmB1 hydrolase superfamily ABB07_01880 365 dihydrolipoamide alpha/beta hydrolase, Streptomyces fragilis (WP_108952935.1); 62/72 AbyA5 AbsA5 AbmA5 acyltransferase-like protein ABB07_01885 69 hypothetical protein hypothetical protein, Streptomyces hokutonensis (WP_019071716.1); 51/61 - - ABB07_01890 256 hypothetical protein activator protein, Actinocrispum wychmicini (WP_132114020.1); 62/75 AbyI - AbmI ABB07_01895 260 hypothetical protein thioesterase, Streptomyces paucisporeus (WP_073501301.1); 67/75 AbyT AbsN AbmT methoxymalonyl-ACP ABB07_01900 619 HAD-IIIC family phosphatase, Streptomyces formicae (WP_098241224.1); 64/73 AbyA2 AbsA2 AbmA2 biosynthesis protein FkbH ABB07_01905 88 hypothetical protein acyl carrier protein, Streptomyces sp. CNQ329 (WP_027774411.1); 58/75 AbyA3 AbsA3 AbmA3 ABB07_01910 172 hypothetical protein flavin reductase, Nocardiopsis potens (WP_017592460.1); 60/72 AbyZ AbsH1 AbmZ

115 116 Table S70. Predicted functions of ORFs in abyssomicin BGC from Streptomyces sp. NRRL F-6491 (NZ_LGEE01000251 and NZ_LGEE01000286).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog DsbA family oxidoreductase, Streptomyces sp. CNH287 (WP_027750659.1); ADL06_RS28345 175 hypothetical protein - - - 82/88 ADL06_RS28350 94 hypothetical protein - - - - ADL06_RS28355 63 hypothetical protein MFS transporter, Streptomyces sp. Or20 (WP_097967670.1); 71/74 AbyD AbsD AbmD 4'-phosphopantetheinyl transferase 4'-phosphopantetheinyl transferase superfamily protein, Streptomyces sp. S1 ADL06_RS28360 212 - - - superfamily protein (WP_121827868.1); 93/95 3-oxoacyl-ACP synthase III family ADL06_RS28365 349 AbsA1, Streptomyces sp. LC-6-2 (ARE67857.1); 87/91 AbyA1 AbsA1 AbmA1 protein ADL06_RS28370 81 acyl carrier protein AbsA3, Streptomyces sp. LC-6-2 (ARE67856.1); 75/84 AbyA3 AbsA3 AbmA3 ADL06_RS28375 251 acyltransferase AbsA4, Streptomyces sp. LC-6-2 (ARE67855.1); 90/94 AbyA4 AbsA4 AbmA4 ADL06_RS28380 370 alpha/beta hydrolase AbsA5, Streptomyces sp. LC-6-2 (ARE67854.1); 83/86 AbyA5 AbsA5 AbmA5 ADL06_RS28385 274 thioesterase thioesterase, Streptomyces sp. E14 (WP_009191660.1); 80/83 AbyT AbsN AbmT ADL06_RS28390 - PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 80/84 AbyB1 AbsB1 AbmB1 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// ADL06_RS34415 - PKS I AbsB1, Streptomyces sp. LC-6-2 (ARE67853.1); 74/78 AbyB1 AbsB1 AbmB1 ADL06_RS36865 - PKS I - PKS I PKS I PKS I SDR family NAD(P)-dependent oxidoreductase, partial, Microbispora triticiradicis ADL06_RS34420 - PKS I PKS I PKS I PKS I (WP_117408275.1); 64/71 ADL06_RS34425 - PKS I AbsB3, Streptomyces sp. LC-6-2 (ARE67851.1); 78/84 AbyB3 AbsB3 AbmB3 ADL06_RS34430 652 HAD-IIIC family phosphatase AbsA2, Streptomyces sp. LC-6-2 (ARE67850.1); 81/86 AbyA2 AbsA2 AbmA2 LLM class flavin-dependent ADL06_RS34435 320 AbsE, Streptomyces sp. LC-6-2 (ARE67849.1); 90/94 AbyE AbsE AbmE1 oxidoreductase ABC transporter substrate-binding ADL06_RS34440 551 AbsF1, Streptomyces sp. LC-6-2 (ARE67848.1); 84/90 AbyF1 AbsF1 AbmF1 protein ABC transporter permease, Streptomyces sp. Amel2xE9 (WP_019985558.1); ADL06_RS34445 334 ABC transporter permease AbyF2 AbsF2 AbmF2 82/90 ADL06_RS34450 269 ABC transporter permease AbsF3, Streptomyces sp. LC-6-2 (ARE67846.1); 90/92 AbyF3 AbsF3 AbmF3 ADL06_RS34455 551 ABC transporter ATP-binding protein AbsF4, Streptomyces sp. LC-6-2 (ARE67845.1); 86/89 AbyF4 AbsF4 AbmF4 ADL06_RS34460 395 cytochrome P450 cytochrome P450, Streptomyces sp. Amel2xE9 (WP_027758724.1); 93/96 AbyV AbsV AbmV ADL06_RS34465 68 ferredoxin AbsG1, Streptomyces sp. LC-6-2 (ARE67843.1); 84/94 - AbsG1 AbmG ADL06_RS34470 395 acyltransferase AbsI, Streptomyces sp. LC-6-2 (ARE67842.1); 84/88 - AbsI -

117 ADL06_RS34475 403 cytochrome P450 AbsX, Streptomyces sp. LC-6-2 (ARE67841.1); 91/94 AbyX AbsX - ADL06_RS34480 69 ferredoxin AbsG2, Streptomyces sp. LC-6-2 (ARE67840.1); 89/95 - AbsG2 - ADL06_RS34485 346 aldo/keto reductase aldo/keto reductase, Streptomyces sp. Amel2xE9 (WP_020657195.1); 84/88 - AbsJ AbmJ ADL06_RS34490 171 Diels-Alderase AbsU, Streptomyces sp. LC-6-2 (ARE67838.1); 92/97 AbyU AbsU AbmU TetR/AcrR family transcriptional ADL06_RS34495 199 AbsC2, Streptomyces sp. LC-6-2 (ARE67837.1); 90/94 - AbsC2 - regulator ADL06_RS34500 476 MFS transporter AbsD, Streptomyces sp. LC-6-2 (ARE67836.1); 88/92 AbyD AbsD AbmD

118 Table S71. Predicted functions of ORFs in potential BGC from Streptomyces olivaceus KLBMP 5084 (NZ_CP016795.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog BC342_RS34475 260 thioesterase thioesterase, Streptomyces qinglanensis (WP_069991949.1); 81/87 - - - BC342_RS34480 367 serine hydrolase serine hydrolase, Streptomyces longwoodensis (WP_067241675.1); 83/90 - - - BC342_RS34485 382 homoserine O-acetyltransferase homoserine O-acetyltransferase, Streptomyces sp. E14 (EFF89200.1); 86/90 - - - bifunctional o-acetylhomoserine/o- bifunctional o-acetylhomoserine/o-acetylserine sulfhydrylase, Streptomyces sp. BC342_RS34490 453 - - - acetylserine sulfhydrylase XY006 (WP_094053066.1); 91/96 BC342_RS34495 201 dihydrofolate reductase dihydrofolate reductase, Streptomyces sp. CB01635 (WP_100599268.1); 87/95 - - - response regulator transcription response regulator transcription factor, Streptomyces sp. NRRL F-5639 BC342_RS34500 269 - - - factor (WP_051705713.1); 53/65 aldo/keto reductase family aldo/keto reductase family oxidoreductase, Streptomyces sp. FXJ7.023 BC342_RS34505 290 - - - oxidoreductase (WP_037772516.1); 99/99 helix-turn-helix transcriptional BC342_RS34510 148 transcriptional regulator, Streptomyces sp. FXJ7.023 (WP_037772514.1); 99/100 - - - regulator helix-turn-helix transcriptional BC342_RS34515 94 transcriptional regulator, Brevibacterium aurantiacum (WP_096147035.1); 72/90 - - - regulator NADH:flavin oxidoreductase/NADH NADH:flavin oxidoreductase/NADH oxidase, Corynebacterium sputi BC342_RS34520 363 - - - oxidase (WP_027019135.1); 69/80 XRE family transcriptional regulator, Streptomyces viridosporus BC342_RS34525 745 transcriptional regulator - - - (WP_081238662.1); 83/88 BC342_RS34530 185 hypothetical protein hypothetical protein, Streptomyces sp. Root369 (WP_057616167.1); 91/96 - - - BC342_RS34535 191 hypothetical protein hypothetical protein, Streptomyces sp. FXJ7.023 (WP_037772510.1); 99/99 - - - methyltransferase domain-containing protein, Streptomyces sp. FXJ7.023 BC342_RS34540 276 PKS I - - - (WP_037772509.1); 99/99 acyltransferase domain-containing protein, Streptomyces sp. E5N91 SAI-083 BC342_RS34545 1364 PKS I - - - (WP_123627584.1); 95/96 BC342_RS34550 308 PKS I acyl transferase, partial, Streptomyces varsoviensis (KOG86991.1); 90/91 - - - pyridoxamine 5'-phosphate oxidase pyridoxamine 5'-phosphate oxidase family protein, Streptomyces sp. FXJ7.023 BC342_RS34555 173 - - - family protein (WP_037772507.1); 99/100 BC342_RS34560 2799 PKS I type I polyketide synthase, Streptomyces cattleya (WP_014140914.1); 87/90 - - - SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. E5N91 SAI- BC342_RS34565 6128 PKS I - - - 083 (WP_123627588.1); 96/97 hypothetical protein, Streptomyces sp. E5N91 SAI-083 (WP_123627591.1); BC342_RS34570 140 Diels-Alderase AbyU AbsU AbmU 98/99 nuclear transport factor 2 family nuclear transport factor 2 family protein, Streptomyces sp. E5N91 SAI-083 BC342_RS34575 133 - - - protein (WP_123627590.1); 95/97 BC342_RS34580 416 hypothetical protein cytochrome P450, Streptomyces sp. E5N91 SAI-083 (WP_123627589.1); 97/98 - - - NAD(P)-dependent oxidoreductase, Streptomyces sp. FXJ7.023 BC342_RS34585 280 NAD(P)-dependent oxidoreductase - - - (WP_037772598.1); 99/100

119 nuclear transport factor 2 family nuclear transport factor 2 family protein, Streptomyces sp. E5N91 SAI-083 BC342_RS34590 157 - - - protein (WP_123627593.1); 98/99 BC342_RS34595 273 thioesterase thioesterase, Streptomyces cattleya (WP_014140907.1); 85/90 - - - BC342_RS34600 408 cytochrome P450 cytochrome P450, Streptomyces sp. E5N91 SAI-083 (WP_123627594.1); 98/98 - - - hypothetical protein EDC84_6803, Streptomyces sp. E5N91 SAI-083 BC342_RS36425 99 hypothetical protein - - - (ROO97925.1); 94/94 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces sp. E5N91 SAI-083 BC342_RS34605 393 - - - oxidoreductase (WP_123627595.1); 98/99 SDR family oxidoreductase, Streptomyces sp. E5N91 SAI-083 BC342_RS34610 277 SDR family oxidoreductase - - - (WP_123627596.1); 98/98

120 Table S72. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces regalis NRRL 3151 (NZ_LLZG01000385).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) AfsR/SARP family transcriptional ADL12_RS39130 257 activator protein, Streptomyces regensis (KMS84432.1); 89/94 AbyI/AbyR - AbmI regulator thioesterase, Streptomyces sp. NRRL WC-3744 (WP_063743390.1); ADL12_RS39135 257 thioesterase AbyT AbsN AbmT 67/75 helix-turn-helix transcriptional regulator, Streptomyces sp. NRRL ADL12_RS39140 909 LuxR family transcriptional regulator AbyH - AbmH WC-3744 (WP_106978307.1); 74/82 ADL12_RS39145 860 RHS repeat protein RHS repeat protein, Streptomyces fragilis (WP_108953524.1); 72/79 AbyK - - ADL12_RS39150 134 Diels-Alderase hypothetical protein, Streptomyces fragilis (WP_108952931.1); 91/94 AbyU AbsU AbmU 3-oxoacyl-ACP synthase III family 3-oxoacyl-ACP synthase, Streptomyces regensis (KMS84435.1); ADL12_RS39155 344 AbyA1 AbsA1 AbmA1 protein 89/93 HAD-IIIC family phosphatase, Streptomyces sp. NRRL WC-3744 ADL12_RS39160 589 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 (WP_078630008.1); 83/88 acyl carrier protein, Streptomyces sp. NRRL WC-3725 ADL12_RS39165 75 hypothetical protein AbyA3 AbsA3 AbmA3 (WP_031029037.1); 92/94 acyltransferase, Streptomyces sp. NRRL WC-3744 ADL12_RS39170 255 acyltransferase AbyA4 AbsA4 AbmA4 (WP_051816343.1); 84/91 hydrolase superfamily dihydrolipoamide acyltransferase-like protein, ADL12_RS39175 360 alpha/beta hydrolase AbyA5 AbsA5 AbmA5 Streptomyces regensis (KMS84437.1); 87/89 ADL12_RS39180 166 flavin reductase flavin oxidoreductase, Streptomyces regensis (KMS84438.1); 84/90 AbyZ AbsH1 AbmZ TetR/AcrR family transcriptional TetR family transcriptional regulator, Streptomyces sp. NRRL WC- ADL12_RS39185 227 AbyC - AbmC regulator 3723 (KOV74725.1); 89/95 DHA2 family efflux MFS transporter DHA2 family efflux MFS transporter permease subunit, ADL12_RS39190 483 AbyD AbsD AbmD permease subunit Streptomyces sp. NRRL WC-3744 (WP_030991264.1); 89/93 LLM class flavin-dependent FMN-linked alkanal monooxygenase, Streptomyces regensis ADL12_RS39195 345 AbyE AbsE AbmE1 oxidoreductase (KMS84441.1); 89/94 ABC transporter substrate-binding ABC transporter substrate-binding protein, Streptomyces fragilis ADL12_RS39200 543 AbyF1 AbsF1 AbmF1 protein (WP_108952939.1); 78/86 ABC transporter permease, Streptomyces regensis (KMS84443.1); ADL12_RS39205 316 ABC transporter permease AbyF2 AbsF2 AbmF2 87/92 ABC transporter permease, Streptomyces fragilis ADL12_RS39210 291 ABC transporter permease AbyF3 AbsF3 AbmF3 (WP_108952941.1); 81/88 ABC transporter ATP-binding protein, Streptomyces fragilis ADL12_RS39215 548 ABC transporter ATP-binding protein AbyF4 AbsF4 AbmF4 (WP_108952942.1); 82/87 acyltransferase, Streptomyces sp. NRRL WC-3725 ADL12_RS39220 389 acyltransferase - AbsI - (WP_031029026.1); 87/90 ADL12_RS39225 406 cytochrome P450 cytochrome P450, Streptomyces regensis (KMS84447.1); 90/93 AbyV/AbyX AbsV/AbsX AbmV ADL12_RS39230 64 ferredoxin ferredoxin, Streptomyces regensis (KMS84448.1); 92/95 - AbsG2/AbsG1 AbmG ADL12_RS39235 305 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces regensis (KMS84449.1); 89/91 - - -

121 type I polyketide synthase, Streptomyces sp. 2131.1 ADL12_RS39240 - PKS I PKS I PKS I PKS I (WP_093709985.1); 68/76

122 Table S73. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces regensis NRRL B-11479 (LFVR01000395.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) ACZ91_4783 hypothetical protein, Streptomyces sp. NRRL WC-3744 69 hypothetical protein - - - 5 (WP_030991280.1); 100/100 ACZ91_4784 activator protein, Streptomyces sp. NRRL WC-3725 257 activator protein AbyI - AbmI 0 (WP_031029046.1); 100/100 ACZ91_4785 helix-turn-helix transcriptional regulator, Streptomyces sp. NRRL 914 hypothetical protein AbyH - AbmH 0 WC-3725 (WP_107054736.1); 99/99 ACZ91_4785 882 hypothetical protein RHS repeat protein, Streptomyces fragilis (WP_108953524.1); 76/81 AbyK - - 5 ACZ91_4786 134 Diels-Alderase hypothetical protein, Streptomyces fragilis (WP_108952931.1); 95/95 AbyU AbsU AbmU 0 ACZ91_4786 3-oxoacyl-ACP synthase, Streptomyces antibioticus (KOG62350.1); 344 3-oxoacyl-ACP synthase AbyA1 AbsA1 AbmA1 5 100/100 ACZ91_4787 methoxymalonyl-ACP biosynthesis HAD-IIIC family phosphatase, Streptomyces sp. NRRL WC-3725 630 AbyA2 AbsA2 AbmA2 0 protein FkbH (WP_078918059.1); 99/99 ACZ91_4787 acyl carrier protein, Streptomyces antibioticus (KOG62349.1); 75 acyl carrier protein AbyA3 AbsA3 AbmA3 5 100/100 ACZ91_4788 acyltransferase, Streptomyces sp. NRRL WC-3744 246 acyltransferase AbyA4 AbsA4 AbmA4 0 (WP_051816343.1); 99/99 ACZ91_4788 hydrolase superfamily dihydrolipoamide hydrolase superfamily dihydrolipoamide acyltransferase-like protein, 360 AbyA5 AbsA5 AbmA5 5 acyltransferase-like protein Streptomyces antibioticus (KOG62348.1); 100/100 ACZ91_4789 flavin oxidoreductase, Streptomyces sp. NRRL WC-3723 172 flavin oxidoreductase AbyZ AbsH1 AbmZ 0 (KOV74748.1); 99/100 ACZ91_4789 TetR/AcrR family transcriptional regulator, Streptomyces sp. NRRL 227 TetR family transcriptional regulator AbyC - AbmC 5 WC-3744 (WP_030991266.1); 99/100 ACZ91_4790 EmrB/QacA family drug resistance EmrB/QacA family drug resistance transporter, Streptomyces 483 AbyD AbsD AbmD 0 transporter antibioticus (KOG62345.1); 100/100 ACZ91_4790 FMN-linked alkanal monooxygenase, Streptomyces antibioticus 345 FMN-linked alkanal monooxygenase AbyE AbsE AbmE1 5 (KOG62344.1); 100/100 ACZ91_4791 ABC transporter substrate-binding ABC transporter substrate-binding protein, Streptomyces antibioticus 544 AbyF1 AbsF1 AbmF1 0 protein (KOG62343.1); 100/100 ACZ91_4791 ABC transporter permease, Streptomyces sp. NRRL WC-3744 315 ABC transporter permease AbyF2 AbsF2 AbmF2 5 (WP_030991259.1); 99/100 ACZ91_4792 peptide ABC transporter permease, Streptomyces antibioticus 291 peptide ABC transporter permease AbyF3 AbsF3 AbmF3 0 (KOG62341.1); 100/100 ACZ91_4792 ABC transporter ATP-binding protein, Streptomyces antibioticus 544 ABC transporter ATP-binding protein AbyF4 AbsF4 AbmF4 5 (KOG62340.1); 100/100 ACZ91_4793 acyltransferase, Streptomyces antibioticus (WP_053212164.1); 388 hypothetical protein - AbsI - 0 100/100 ACZ91_4793 cytochrome P450, Streptomyces antibioticus (KOG62338.1); 406 cytochrome P450 AbyV/AbyX AbsV/AbsX AbmV 5 100/100 ACZ91_4794 64 ferredoxin ferredoxin, Streptomyces antibioticus (KOG62337.1); 100/100 - AbsG2/AbsG1 AbmG 0

123 ACZ91_4794 alpha/beta hydrolase, Streptomyces antibioticus (KOG62336.1); 294 alpha/beta hydrolase - - - 5 100/100 Table S74. Predicted functions of ORFs in potential abyssomicin BGC from Saccharothrix syringae NRRL B-16468 (NZ_JNYO01000044.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) OQ01_RS3719 hypothetical protein, Actinoplanes regularis (WP_089299276.1); 262 hypothetical protein - - - 5 32/46 OQ01_RS4895 TetR/AcrR family transcriptional regulator, Nocardia sp. NRRL S- 223 TetR/AcrR family transcriptional regulator - AbsC1 - 5 836 (WP_053731530.1); 82/88 OQ01_RS3720 alpha/beta hydrolase, Nocardia sp. NRRL S-836 295 alpha/beta hydrolase - - - 5 (WP_053731531.1); 65/83 OQ01_RS3721 251 SDR family oxidoreductase 3-oxoacyl-ACP reductase, Frankia coriariae (KLL10339.1); 61/73 - AbsM - 0 OQ01_RS3721 TetR/AcrR family transcriptional regulator, Microbispora sp. GKU 200 TetR/AcrR family transcriptional regulator - AbsC2 - 5 823 (WP_079317081.1); 62/73 OQ01_RS3722 MFS transporter, Microbispora sp. GKU 823 (WP_079317079.1); 470 MFS transporter AbyD AbsD AbmD 0 65/80 OQ01_RS3722 LLM class flavin-dependent Nitrilotriacetate monooxygenase, Frankia alni ACN14a 438 - - - 5 oxidoreductase (CAJ58912.1); 74/83 OQ01_RS3723 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia alni 341 AbyE AbsE AbmE1 0 oxidoreductase (WP_011601492.1); 74/82 OQ01_RS3723 ABC-type transporter, periplasmic subunit, Frankia symbiont of 551 ABC transporter substrate-binding protein AbyF1 AbsF1 AbmF1 5 Datisca glomerata (AEH09361.1); 66/80 OQ01_RS3724 ABC transporter permease, Frankia symbiont of Coriaria 305 ABC transporter permease AbyF2 AbsF2 AbmF2 0 ruscifolia (WP_131785888.1); 72/83 OQ01_RS3724 ABC transporter permease subunit, Frankia symbiont of Coriaria 278 ABC transporter permease AbyF3 AbsF3 AbmF3 5 ruscifolia (WP_131785887.1); 74/86 OQ01_RS3725 ABC transporter ATP-binding protein, Frankia sp. BMG5.30 516 ABC transporter ATP-binding protein AbyF4 AbsF4 AbmF4 0 (WP_076844589.1); 67/77 OQ01_RS3725 hypothetical protein, Saccharothrix australiensis 242 hypothetical protein - - - 5 (WP_121006568.1); 61/70 OQ01_RS3726 flavin reductase, Actinomadura sp. NEAU-Ht49 168 flavin reductase AbyZ AbsH1 AbmZ 0 (WP_122194805.1); 62/73 OQ01_RS3726 acyl carrier protein, Streptomyces malaysiense 79 acyl carrier protein AbyA3 AbsA3 AbmA3 5 (WP_071387400.1); 53/76 OQ01_RS3727 HAD-IIIC family phosphatase, Kutzneria buriramensis 618 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 0 (WP_116181645.1); 66/76 OQ01_RS3727 activator protein, Kutzneria buriramensis (WP_116181646.1); 253 hypothetical protein AbyI - AbmI 5 68/84 OQ01_RS3728 LuxR family transcriptional regulator, Rhodococcus yunnanensis 913 hypothetical protein AbyH - AbmH 0 (WP_072806082.1); 40/57 OQ01_RS3728 propionyl-CoA carboxylase subunit beta, Streptomyces 460 propionyl-CoA carboxylase subunit beta - - - 5 cellostaticus (WP_079058127.1); 70/78 OQ01_RS3729 330 aldo/keto reductase aldo/keto reductase, Frankia coriariae (WP_047223142.1); 75/84 - AbsJ AbmJ 0

124 OQ01_RS3729 hypothetical protein FrCorBMG51_12000, Frankia coriariae 125 Diels-Alderase AbyU AbsU AbmU 5 (KLL11361.1); 80/85 OQ01_RS3730 pimaricinolide synthase PimS1, Kutzneria buriramensis 1323 PKS I AbyB3 AbsB3 AbmB3 0 (REH39151.1); 67/74 OQ01_RS3730 SDR family NAD(P)-dependent oxidoreductase, Kutzneria 3369 PKS I AbyB2 AbsB2 AbmB2 5 buriramensis (WP_116178516.1); 59/69 OQ01_RS4729 type I polyketide synthase, Streptomyces fragilis 5489 PKS I 5 (WP_108952947.1); 55/64 AbyB1 AbsB1 AbmB1 OQ01_RS5097 type I polyketide synthase, partial, Streptomyces sp. 4R-3d 256 PKS I 5 (WP_135068668.1); 72/81 OQ01_RS3731 alpha/beta hydrolase, Kutzneria buriramensis 339 alpha/beta hydrolase AbyA5 AbsA5 AbmA5 5 (WP_116181688.1); 66/74 OQ01_RS3732 215 hypothetical protein acyltransferase, Frankia sp. BMG5.30 (WP_076843553.1); 73/79 AbyA4 AbsA4 AbmA4 0 OQ01_RS3732 345 3-oxoacyl-ACP synthase III family protein 3-oxoacyl-ACP synthase, Frankia coriariae (KLL11317.1); 78/85 AbyA1 AbsA1 AbmA1 5 OQ01_RS3733 monooxygenase FAD-binding protein, Frankia symbiont of 491 hypothetical protein - - - 0 Datisca glomerata (AEH09375.1); 57/64 OQ01_RS3733 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Kutzneria 353 - - AbmE2 5 oxidoreductase buriramensis (WP_116181640.1); 70/81 OQ01_RS3734 399 cytochrome P450 cytochrome P450, Frankia coriariae (KLL11355.1); 73/84 AbyV AbsV AbmV 0 OQ01_RS3734 ferredoxin, Streptomyces sp. NRRL WC-3742 68 ferredoxin AbyW AbsG2/AbsG1 AbmG 5 (WP_078911468.1); 68/82 OQ01_RS3735 alpha/beta hydrolase, Saccharothrix texasensis 313 alpha/beta hydrolase - - - 0 (WP_123742887.1); 67/75

125 Table S75. Predicted functions of ORFs in potential BGC from Saccharothrix syringae NRRL B-16468 (NZ_JNYO01000017.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog OQ01_RS21070 406 riboflavin synthase riboflavin synthase, Nonomuraea polychroma (WP_127932388.1); 81/89 - - - class I SAM-dependent methyltransferase domain-containing protein, Nonomuraea polychroma OQ01_RS21075 282 - - - methyltransferase (WP_127932389.1); 76/83 hypothetical protein, Saccharothrix sp. NRRL B-16314 (WP_033438186.1); OQ01_RS21080 131 hypothetical protein - - - 73/79 sigma-70 family RNA polymerase sigma sigma-70 family RNA polymerase sigma factor, Lentzea jiangxiensis OQ01_RS21085 184 - - - factor (WP_090097117.1); 94/96 OQ01_RS21090 344 hypothetical protein hypothetical protein, Lechevalieria atacamensis (WP_112227485.1); 82/90 - - - serine/threonine protein kinase, Saccharothrix carnea (WP_106615887.1); OQ01_RS21095 378 serine/threonine protein kinase - - - 70/75 MarR family transcriptional regulator, Actinokineospora inagensis OQ01_RS21100 224 ArsR family transcriptional regulator - - - (WP_026421213.1); 81/86 arsenate reductase ArsC, Streptomyces megasporus (WP_031511409.1); OQ01_RS21105 157 arsenate reductase ArsC - - - 88/94 FAD-dependent oxidoreductase, Saccharothrix sp. ALI-22-I OQ01_RS21110 446 FAD-dependent oxidoreductase - - - (WP_077008908.1); 82/86 metalloregulator ArsR/SmtB family L-amino acid N-acyltransferase YncA, Saccharothrix variisporea OQ01_RS21115 294 - - - transcription factor (RKT67768.1); 86/91 nuclear transport factor 2 family protein, Streptomyces iranensis OQ01_RS21120 153 nuclear transport factor 2 family protein - - - (WP_078957437.1); 87/92 NAD(P)-dependent oxidoreductase, Streptomyces iranensis OQ01_RS21125 281 NAD(P)-dependent oxidoreductase - - - (WP_078957138.1); 87/93 OQ01_RS21130 140 Diels-Alderase hypothetical protein, Streptomyces iranensis (WP_078957139.1); 88/97 AbyU AbsU AbmU nuclear transport factor 2 family protein, Streptomyces cattleya OQ01_RS21135 119 nuclear transport factor 2 family protein - - - (WP_014627233.1); 92/98 OQ01_RS21140 417 cytochrome P450 cytochrome P450, Streptomyces iranensis (WP_044580004.1); 93/95 - - - type I polyketide synthase, Streptomyces iranensis (WP_044580005.1); OQ01_RS21145 6097 PKS I - - - 89/92 type I polyketide synthase, Streptomyces cattleya (WP_014140914.1); OQ01_RS21150 4278 PKS I - - - 83/88 pyridoxamine 5'-phosphate oxidase family protein, Streptomyces iranensis OQ01_RS21155 175 hypothetical protein - - - (WP_044580008.1); 88/94 type I polyketide synthase, Streptomyces iranensis (WP_044580009.1); OQ01_RS21160 3933 PKS I - - - 89/93 type I polyketide synthase, Streptomyces iranensis (WP_044580010.1); OQ01_RS21165 1385 PKS I - - - 89/92 crotonyl-CoA carboxylase/reductase, Streptomyces xiamenensis OQ01_RS21170 448 crotonyl-CoA carboxylase/reductase - - - (WP_046722665.1); 79/89 ketoacyl-ACP synthase III, Saccharothrix sp. NRRL B-16314 OQ01_RS21175 336 ketoacyl-ACP synthase III - - - (WP_081915703.1); 72/82

126 3-hydroxybutyryl-CoA dehydrogenase, Amycolatopsis sp. 8-3EHSu OQ01_RS21180 292 3-hydroxybutyryl-CoA dehydrogenase - - - (WP_130478881.1); 63/78 OQ01_RS21185 408 cytochrome P450 cytochrome P450, Streptomyces iranensis (WP_078957143.1); 83/90 - - - OQ01_RS21190 68 thioesterase thioesterase, Streptomyces cattleya (WP_014140907.1); 87/91 - - - LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces iranensis OQ01_RS21195 393 - - - oxidoreductase (WP_044580012.1); 93/96 SDR family oxidoreductase, Streptomyces cattleya (WP_014140897.1); OQ01_RS21200 277 SDR family oxidoreductase - - - 91/94 IS5 family transposase, Actinosynnema sp. ALI-1.44 (WP_076986720.1); OQ01_RS50340 128 hypothetical protein - - - 38/41 OQ01_RS21205 186 barstar family protein barnase inhibitor, Micromonospora saelicesensis (WP_112675927.1); 74/81 - - - OQ01_RS50345 40 hypothetical protein - - - - glutathione-dependent formaldehyde glutathione-dependent formaldehyde dehydrogenase, Actinomadura fibrosa OQ01_RS21210 390 - - - dehydrogenase (WP_131759867.1); 78/87 hypothetical protein, Streptosporangium sp. 'caverna' (WP_110699844.1); OQ01_RS21215 158 hypothetical protein - - - 52/65

127 Table S76. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces sp. SCA2-2 (NZ_PKMX01000004 and NZ_PKMX01000005).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog C0L86_RS0552 981 hypothetical protein AbmH, Streptomyces koyangensis (AVI57436.1); 99/99 AbyH - AbmH 0 C0L86_RS0552 1040 PKS I AbmB3, Streptomyces koyangensis (AVI57435.1); 99/99 AbyB3 AbsB3 AbmB3 5 C0L86_RS0553 - PKS I AbmB2, Streptomyces koyangensis (AVI57434.1); 99/99 AbyB2 AbsB2 AbmB2 0 //////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////////// C0L86_RS0553 - PKS I AbmB1, Streptomyces koyangensis (AVI57433.1); 99/99 AbyB1 AbsB1 AbmB1 5 C0L86_RS0554 178 flavin reductase family protein flavin reductase, Streptomyces sp. Ru62 (WP_103810817.1); 58/71 AbyZ AbsH1 AbmZ 0 C0L86_RS0554 274 alpha/beta fold hydrolase AbmT, Streptomyces koyangensis (AVI57431.1); 99/99 AbyT AbsN AbmT 5 C0L86_RS0555 373 alpha/beta hydrolase AbmA5, Streptomyces koyangensis (AVI57430.1); 99/99 AbyA5 AbsA5 AbmA5 0 C0L86_RS0555 280 acyltransferase AbmA4, Streptomyces koyangensis (AVI57429.1); 99/100 AbyA4 AbsA4 AbmA4 5 C0L86_RS0556 75 acyl carrier protein acyl carrier protein, Streptomyces malaysiense (WP_071387400.1); 63/78 AbyA3 AbsA3 AbmA3 0 C0L86_RS0556 628 HAD-IIIC family phosphatase AbmA2, Streptomyces koyangensis (AVI57427.1); 99/99 AbyA2 AbsA2 AbmA2 5 C0L86_RS0557 343 3-oxoacyl-ACP synthase III family protein AbmA1, Streptomyces koyangensis (AVI57426.1); 99/99 AbyA1 AbsA1 AbmA1 0 C0L86_RS0557 DHA2 family efflux MFS transporter 482 AbmD, Streptomyces koyangensis (AVI57425.1); 99/99 AbyD AbsD AbmD 5 permease subunit C0L86_RS0558 353 MsnO8 family LLM class oxidoreductase AbmE1, Streptomyces koyangensis (AVI57424.1); 99/99 AbyE AbsE AbmE1 0 C0L86_RS0558 TetR/AcrR family transcriptional regulator, Streptomyces regalis 257 TetR/AcrR family transcriptional regulator AbyC - AbmC 5 (WP_062712137.1); 62/75 C0L86_RS0559 405 cytochrome P450 cytochrome P450, Streptomyces sp. 4R-3d (WP_135068654.1); 69/80 AbyV AbsV AbmV 0 C0L86_RS0559 70 ferredoxin AbmG, Streptomyces koyangensis (AVI57421.1); 99/100 - AbsG1 AbmG 5 C0L86_RS0560 308 aldo/keto reductase AbmJ, Streptomyces koyangensis (AVI57420.1); 99/99 - AbsJ AbmJ 0 C0L86_RS0560 546 ABC transporter substrate-binding protein AbmF1, Streptomyces koyangensis (AVI57419.1); 99/99 AbyF1 AbsF1 AbmF1 5 C0L86_RS0561 313 ABC transporter permease ABC transporter permease, Streptomyces sp. 4R-3d (TFI25402.1); 69/82 AbyF2 AbsF2 AbmF2 0 C0L86_RS0561 413 amidohydrolase family protein AbmM, Streptomyces koyangensis (AVI57417.1); 99/99 - - AbmM 5 C0L86_RS0562 298 ABC transporter permease ABC transporter permease, Actinomadura macra (WP_067456459.1); AbyF3 AbsF3 AbmF3

128 0 63/80 C0L86_RS0562 dipeptide ABC transporter ATP-binding 561 AbmF4, Streptomyces koyangensis (AVI57415.1); 99/98 AbyF4 AbsF4 AbmF4 5 protein C0L86_RS0563 281 metallophosphoesterase AbmL, Streptomyces koyangensis (AVI57414.1); 99/99 - - AbmL 0 C0L86_RS0563 4'-phosphopantetheinyl transferase 253 AbmK, Streptomyces koyangensis (AVI57413.1); 97/97 - AbmK 5 superfamily protein C0L86_RS0564 219 Diels-Alderase AbmU, Streptomyces koyangensis (AVI57412.1); 99/99 AbyU AbsU AbmU 0 C0L86_RS0564 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Saccharothrix syringae 356 - - AbmE2 5 oxidoreductase (WP_033434377.1); 57/67 C0L86_RS0565 256 activator protein AbmI, Streptomyces koyangensis (AVI57410.1); 99/100 AbyI - AbmI 0

129 Table S77. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces sp. SolWspMP-5a-2 (NZ_FMCI01000204).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog DHA2 family efflux MFS transporter permease subunit, Streptomyces sp. GA0115242_RS20650 510 MFS transporter - - - NRRL F-5126 (WP_078849779.1); 91/95 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Streptomyces sp. NRRL F-5126 GA0115242_RS20655 196 - - - regulator (WP_078849780.1); 90/95 hypothetical protein, Streptomyces sp. NRRL F-5126 (WP_030904229.1); GA0115242_RS20660 493 hypothetical protein - - - 90/93 hypothetical protein, Streptomyces sp. NRRL F-5126 (WP_030904231.1); GA0115242_RS20665 131 Diels-Alderase AbyU AbsU AbmU 91/94 GA0115242_RS20670 77 hypothetical protein - - - - 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. NRRL F-5126 GA0115242_RS20675 343 - - - family protein (WP_030904235.1); 97/99 AfsR/SARP family transcriptional hypothetical protein, Streptomyces sp. NRRL F-5126 (WP_030904237.1); GA0115242_RS20680 265 - - - regulator 93/96 alpha/beta hydrolase, Streptomyces sp. NRRL F-5126 (WP_107059313.1); GA0115242_RS20685 373 alpha/beta hydrolase - - - 90/94 type I polyketide synthase, Streptomyces sp. NRRL F-5126 GA0115242_RS20690 - PKS I - - - (WP_051839911.1); 91/94 type I polyketide synthase, Streptomyces sp. NRRL F-5126 GA0115242_RS20695 - PKS I - - - (WP_051839911.1); 85/87 GA0115242_RS20700 65 ferredoxin ferredoxin, Streptomyces sp. NRRL F-5126 (WP_030904243.1); 89/96 - - - cytochrome P450, Streptomyces sp. NRRL F-5126 (WP_030904245.1); GA0115242_RS20705 410 cytochrome P450 - - - 92/95 GA0115242_RS20710 269 thioesterase thioesterase, Streptomyces sp. NRRL F-5126 (WP_107059319.1); 90/93 - - -

130 Table S78. Predicted functions of ORFs in potential abyssomicin BGC from Streptacidiphilus sp. DSM 106435 (NZ_CP031264.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) NADPH-dependent FMN NADPH-dependent FMN reductase, Streptomyces sp. CB03911 C7M71_RS25195 179 AbyZ AbsH1 AbmZ reductase (WP_073928518.1); 94/96 acyl carrier protein, Streptomyces sp. CB03911 (WP_073928517.1); C7M71_RS25200 81 acyl carrier protein AbyA3 AbsA3 AbmA3 93/95 HAD-IIIC family phosphatase, Streptomyces sp. CB03911 C7M71_RS25205 638 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 (WP_073928516.1); 94/96 hypothetical protein, Streptomyces sp. CB03911 (WP_073928515.1); C7M71_RS25210 67 hypothetical protein - - - 68/73 type I polyketide synthase, Streptomyces sp. CB03911 C7M71_RS25215 697 PKS I (WP_079198462.1); 92/92 type I polyketide synthase, Streptomyces sp. CB03911 C7M71_RS25220 4494 PKS I AbyB1 AbsB1 AbyB1 (WP_079198462.1); 91/93 type I polyketide synthase, Streptomyces sp. CB03911 C7M71_RS25225 1275 PKS I (WP_079198462.1); 91/93 C7M71_RS25230 269 thioesterase thioesterase, Streptomyces sp. CB03911 (WP_079198461.1); 89/91 AbyT AbsN AbmT AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Streptomyces sp. CB03911 C7M71_RS25235 295 AbyI - AbmI regulator (WP_073928514.1); 96/97 alpha/beta hydrolase, Streptomyces sp. CB03911 (WP_073928513.1); C7M71_RS25240 369 alpha/beta hydrolase AbyA5 AbsA5 AbmA5 96/97 acyltransferase, Streptomyces sp. CB03911 (WP_073928512.1); C7M71_RS25245 275 acyltransferase AbyA4 AbsA4 AbmA4 95/97 LuxR family transcriptional LuxR family transcriptional regulator, Streptomyces sp. CB03911 C7M71_RS25250 609 AbyH - AbmH regulator (WP_079198460.1); 91/93 LLM class flavin-dependent oxidoreductase, Streptomyces sp. C7M71_RS25255 225 hypothetical protein - - - CB03911 (WP_073928509.1); 90/92 MFS transporter, Streptomyces sp. CB03911 (WP_073928508.1); C7M71_RS25260 475 MFS transporter AbyD AbsD AbmD 94/95 AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Streptomyces sp. NRRL C7M71_RS25265 281 AbyI - AbmI regulator WC-3742 (WP_063763291.1); 89/93 aldo/keto reductase, Streptomyces sp. CB03911 (WP_073928507.1); C7M71_RS25270 330 aldo/keto reductase - AbsJ AbmJ 98/98 acyltransferase, Streptomyces sp. CB03911 (WP_073928506.1); C7M71_RS25275 388 acyltransferase - AbsI - 91/94 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Streptomyces C7M71_RS25280 483 AbyD AbsD AbmD transporter permease subunit sp. NRRL WC-3742 (WP_037973487.1); 87/93 C7M71_RS25285 69 ferredoxin ferredoxin, Streptomyces sp. CB03911 (WP_073928505.1); 88/94 - AbsG2/AbsG1 AbmG cytochrome P450, Streptomyces sp. CB03911 (WP_079198459.1); C7M71_RS25290 436 cytochrome P450 AbyV AbsV AbmV 98/99 hypothetical protein, Streptomyces sp. CB03911 (WP_073928710.1); C7M71_RS25295 125 Diels-Alderase AbyU AbsU AbmU 92/96 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. CB03911 C7M71_RS25300 343 AbyA1 AbsA1 AbmA1 family protein (WP_073928503.1); 97/97

131 type I polyketide synthase, Streptomyces sp. CB03911 C7M71_RS25305 558 PKS I (WP_073928502.1); 91/93 type I polyketide synthase, Streptomyces sp. CB03911 C7M71_RS25310 91 PKS I (WP_073928502.1); 89/89 AbyB2 AbsB2 AbmB2 type I polyketide synthase, Streptomyces sp. CB03911 C7M71_RS25315 197 PKS I (WP_073928502.1); 88/89 type I polyketide synthase, Streptomyces sp. CB03911 C7M71_RS25320 2670 PKS I (WP_073928502.1); 91/93 type I polyketide synthase, Streptomyces sp. CB03911 C7M71_RS25325 1078 PKS I AbyB3 AbsB3 AbmB3 (WP_079198458.1); 93/95 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces sp. C7M71_RS25330 347 - - AbmE2 oxidoreductase CB03911 (WP_073928501.1); 95/97 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces sp. C7M71_RS25335 341 AbyE AbsE AbmE1 oxidoreductase CB03911 (WP_073928467.1); 95/96 NtaA/DmoA family FMN- LLM class flavin-dependent oxidoreductase, Streptomyces sp. C7M71_RS25340 385 - - - dependent monooxygenase CB03911 (WP_073928466.1); 96/98 ABC transporter ATP-binding ABC transporter ATP-binding protein, Streptomyces sp. CB03911 C7M71_RS25345 628 AbyF4 AbsF4 AbmF4 protein (WP_079198451.1); 95/96 ABC transporter permease, Streptomyces sp. CB03911 C7M71_RS25350 272 ABC transporter permease AbyF3 AbsF3 AbmF3 (WP_073928702.1); 93/97 ABC transporter permease, Streptomyces sp. CB03911 C7M71_RS25355 308 ABC transporter permease AbyF2 AbsF2 AbmF2 (WP_073928465.1); 97/99 ABC transporter substrate- ABC transporter substrate-binding protein, Streptomyces sp. CB03911 C7M71_RS25360 584 AbyF1 AbsF1 AbmF1 binding protein (WP_079198450.1); 93/95 alpha/beta hydrolase, Streptomyces sp. CB03911 (WP_079198449.1); C7M71_RS25365 316 alpha/beta hydrolase - - - 94/95 TetR/AcrR family transcriptional TetR/AcrR family transcriptional regulator, Streptomyces sp. CB03911 C7M71_RS25370 220 AbyC - AbmC regulator (WP_073928463.1); 99/99

132 Table S79. Predicted functions of ORFs surrounding AbyU homolog from Streptomyces hoynatensis KCTC 29097 (NZ_RBAL01000026.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog TetR/AcrR family transcriptional TetR family transcriptional regulator, Actinomadura sp. KC345 (WP_131884222.1); D7294_RS28425 233 - - - regulator 77/86 D7294_RS28430 740 MMPL family transporter membrane protein, Streptomyces olindensis (KDN75573.1); 60/75 - - - AfsR/SARP family transcriptional D7294_RS28435 254 activator protein, Actinomadura sp. 7K534 (WP_132046165.1); 56/69 - - - regulator D7294_RS28440 181 Diels-Alderase hypothetical protein, Streptomyces sp. NRRL S-350 (WP_030245418.1); 34/55 AbyU AbsU AbmU D7294_RS28445 261 thioesterase thioesterase, Streptomyces sp. AZ1-7 (RKN06823.1); 57/68 - - - D7294_RS28450 448 hypothetical protein hypothetical protein, Streptomyces sp. MP131-18 (WP_079251913.1); 72/84 - - - D7294_RS28455 441 glycosyl transferase hypothetical protein, Catenuloplanes japonicus (WP_033345696.1); 50/65 - - - DHA2 family efflux MFS transporter permease subunit, Frankia sp. BMG5.36 D7294_RS28460 503 MFS transporter - - - (WP_071049484.1); 53/68 LLM class F420-dependent LLM class F420-dependent oxidoreductase, Frankia sp. BMG5.36 D7294_RS28465 290 - - - oxidoreductase (WP_071051364.1); 68/78 D7294_RS28470 1550 PKS I polyketide synthase, Streptomyces sp. 211726 (ARM20279.1); 51/62 - - - D7294_RS28475 4001 PKS I VerV, Actinomadura sp. XM-4-3 (AYW35158.1); 60/70 - - - D7294_RS28480 2194 PKS I type I polyketide synthase, Actinomadura macra (WP_067456433.1); 59/69 - - - SDR family NAD(P)-dependent oxidoreductase, partial, Streptomyces sp. WAC D7294_RS28485 584 PKS I - - - 01420 (WP_126896698.1); 57/66 Polyketide synthase dehydratase, partial, Streptomyces sp. MnatMP-M27 D7294_RS28490 373 PKS I - - - (SCG12060.1); 51/62 D7294_RS28495 830 PKS I type I polyketide synthase, Streptomyces sp. SBT349 (WP_053171085.1); 69/79 - - - SDR family NAD(P)-dependent oxidoreductase, Streptacidiphilus neutrinimicus D7294_RS28500 296 PKS I - - - (WP_084729882.1); 68/76

133 Table S80. Predicted functions of ORFs in abyssomicin BGC from Streptomyces sp. 57 (NZ_RCCZ01000005.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog LuxR family transcriptional regulator, Streptomyces regalis (WP_062712128.1); CLZ79_6704 902 regulatory LuxR family protein AbyH - AbmH 52/63 RHS repeat-associated CLZ79_6705 861 RHS repeat protein, Streptomyces fragilis (WP_108953524.1); 59/67 AbyK - - protein CLZ79_6706 135 Diels-Alderase hypothetical protein, Streptomyces regalis (WP_062712130.1); 87/93 AbyU AbsU AbmU 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Frankia sp. EAN1pec (WP_020461027.1); CLZ79_6707 345 AbyA1 AbsA1 AbmA1 family protein 78/88 methoxymalonyl-ACP biosynthesis protein FkbH, Streptomyces regalis CLZ79_6708 633 HAD-IIIC family phosphatase AbyA2 AbsA2 AbmA2 (KUL23675.1); 70/77 CLZ79_6709 75 acyl carrier protein acyl carrier protein, Streptomyces sp. NRRL WC-3725 (WP_031029037.1); 75/85 AbyA3 AbsA3 AbmA3 2-oxoacid dehydrogenase/acyltransferase catalytic subunit, Streptomyces sp. BK438 CLZ79_6710 255 acyltransferase AbyA4 AbsA4 AbmA4 (TCP45291.1); 76/84 CLZ79_6711 362 alpha/beta hydrolase alpha/beta hydrolase, Streptomyces sp. 2131.1 (WP_093709996.1); 81/87 AbyA5 AbsA5 AbmA5 CLZ79_6712 165 flavin reductase flavin reductase, Streptomyces fragilis (WP_108952936.1); 78/85 AbyZ AbsH1 AbmZ TetR/AcrR family TetR/AcrR family transcriptional regulator, Streptomyces sp. KhCrAH-43 CLZ79_6713 223 AbyC - AbmC transcriptional regulator (WP_018522887.1); 86/93 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Streptomyces sp. NRRL WC- CLZ79_6714 482 AbyD AbsD AbmD transporter permease subunit 3744 (WP_030991264.1); 85/91 LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces sp. KhCrAH-43 CLZ79_6715 348 AbyE AbsE AbmE1 oxidoreductase (WP_018522885.1); 77/85 ABC transporter substrate- ABC transporter substrate-binding protein, Streptomyces sp. KhCrAH-43 CLZ79_6716 544 AbyF1 AbsF1 AbmF1 binding protein (WP_018522884.1); 76/84 CLZ79_6717 319 ABC transporter permease ABC transporter permease, Streptomyces sp. CB01249 (WP_073865209.1); 76/87 AbyF2 AbsF2 AbmF2 CLZ79_6718 286 ABC transporter permease ABC transporter permease, Herbidospora cretacea (WP_034385023.1); 77/83 AbyF3 AbsF3 AbmF3 ABC transporter ATP-binding ABC transporter ATP-binding protein, Streptomyces sp. 2131.1 (WP_093709989.1); CLZ79_6719 539 AbyF4 AbsF4 AbmF4 protein 75/83 CLZ79_6720 392 acyltransferase acyltransferase ,Streptomyces sp. KhCrAH-43 (WP_018522880.1); 63/71 - AbsI - CLZ79_6721 407 cytochrome P450 cytochrome P450, Streptomyces fragilis (WP_108952944.1); 84/89 AbyV AbsV AbmV CLZ79_6722 82 ferredoxin ferredoxin, Streptomyces regensis (KMS84448.1); 84/87 - AbmG1 AbmG CLZ79_6723 294 ferredoxin alpha/beta hydrolase, Streptomyces fragilis (WP_108952946.1); 72/80 - - - LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Frankia sp. EAN1pec CLZ79_6724 357 - - AbmE2 oxidoreductase (WP_020461009.1); 56/67 SDR family oxidoreductase, Streptoalloteichus hindustanus (WP_073481867.1); CLZ79_6725 251 SDR family oxidoreductase - - - 55/66 CLZ79_6726 6183 PKS I ype I polyketide synthase, Streptomyces sp. KhCrAH-43 (WP_018522876.1); 64/71 AbyB1 AbsB1 AbmB1

134 CLZ79_RS33565 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. BK438 3864 PKS I AbyB2 AbsB2 AbmB2 (WP_132903672.1); 68/76 CLZ79_RS33570 1017 PKS I type I polyketide synthase, Streptomyces sp. KhCrAH-43 (WP_018522873.1); 72/78 AbyB3 AbsB3 AbmB3 CLZ79_RS33575 406 cytochrome P450 cytochrome P450, Streptomyces sp. BK438 (WP_132903670.1); 80/87 AbyX/AbyV AbsV/AbsX AbmV

135 Table S81. Predicted functions of ORFs in potential abyssomicin BGC from Streptomyces subroseum CGMCC 4.2132 (NZ_FZOD01000006.1).

Size ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) Aby homolog Abs homolog Abm homolog (aa) LLM class flavin-dependent MsnO8 family LLM class oxidoreductase, Microbispora CHC08_RS08495 320 AbyE AbsE AbmE1 oxidoreductase triticiradicis (WP_117408853.1); 85/90 ABC transporter substrate-binding ABC transporter substrate-binding protein, Microbispora CHC08_RS08500 559 AbyF1 AbsF1 AbmF1 protein triticiradicis (WP_117408852.1); 77/84 ABC transporter permease, Microbispora triticiradicis CHC08_RS08505 331 ABC transporter permease AbyF2 AbsF2 AbmF2 (WP_117408849.1); 77/85 CHC08_RS08510 268 ABC transporter permease AbsF3, Streptomyces sp. LC-6-2 (ARE67846.1); 80/88 AbyF3 AbsF3 AbmF3 CHC08_RS08515 555 ABC transporter ATP-binding protein AbsF4, Streptomyces sp. LC-6-2 (ARE67845.1); 73/81 AbyF4 AbsF4 AbmF4 CHC08_RS08525 273 acyltransferase AbsI, Streptomyces sp. LC-6-2 (ARE67842.1); 66/76 - AbsI - cytochrome P450, Microbispora triticiradicis CHC08_RS08530 408 cytochrome P450 AbyX AbsX AbmV (WP_117409466.1); 85/91 ferredoxin, Microbispora triticiradicis (WP_117409458.1); CHC08_RS08535 72 ferredoxin - AbsG2/AbsG1 AbmG 87/91 aldo/keto reductase, Microbispora triticiradicis CHC08_RS08540 332 aldo/keto reductase - AbsJ AbmJ (WP_117409459.1); 82/89 hypothetical protein, Microbispora triticiradicis CHC08_RS08545 128 Diels-Alderase AbyU AbsU AbmU (WP_117409467.1); 90/96 LuxR family transcriptional regulator, Microbispora triticiradicis CHC08_RS08550 928 hypothetical protein AbyH - AbmH (WP_133306130.1); 71/80 TetR/AcrR family transcriptional regulator, Microbispora sp. CHC08_RS08555 198 TetR/AcrR family transcriptional regulator - AbsC2 - GKU 823 (WP_079317081.1); 82/87 MFS transporter, Microbispora sp. GKU 823 CHC08_RS08560 479 MFS transporter AbyD AbsD AbmD (WP_079317079.1); 79/87 AfsR/SARP family transcriptional AfsR/SARP family transcriptional regulator, Microbispora CHC08_RS08565 252 AbyR/AbyI - AbmI regulator triticiradicis (WP_117409463.1); 83/90

136 Table S82. Predicted functions of ORFs in potential BGC from Streptomyces varsoviensis NRRL B-3589 (NZ_JOFN01000010.1).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog IF95_RS0115745 409 MFS transporter MFS transporter, Streptacidiphilus jiangxiensis (WP_042456014.1); 33/51 - - - IF95_RS0115750 1347 PKS I type I polyketide synthase, Streptomyces iranensis (WP_044580010.1); 86/91 - - - IF95_RS0115755 3948 PKS I type I polyketide synthase, Streptomyces cattleya (WP_014140917.1); 90/93 - - - pyridoxamine 5'-phosphate oxidase pyridoxamine 5'-phosphate oxidase family protein, Streptomyces cattleya IF95_RS0115760 172 - - - family protein (WP_014140915.1); 87/93 IF95_RS39245 1594 PKS I type I polyketide synthase, Streptomyces cattleya (WP_014140914.1); 87/90 - - - IF95_RS39250 2101 PKS I type I polyketide synthase, Streptomyces cattleya (WP_014140914.1); 88/91 - - - IF95_RS37565 5303 PKS I type I polyketide synthase, Streptomyces cattleya (WP_014140913.1); 90/92 - - - IF95_RS0115780 416 cytochrome P450 cytochrome P450, Streptomyces sp. E5N91 SAI-083 (WP_123627589.1); 91/95 - - - nuclear transport factor 2 family nuclear transport factor 2 family protein, Streptomyces cattleya IF95_RS0115785 119 - - - protein (WP_014627233.1); 94/96 IF95_RS0115790 140 Diels-Alderase hypothetical protein, Streptomyces cattleya (WP_014140910.1); 96/98 AbyU AbsU AbmU NAD(P)-dependent oxidoreductase, Streptomyces cattleya (WP_014140909.1); IF95_RS0115795 280 NAD(P)-dependent oxidoreductase - - - 93/97 nuclear transport factor 2 family nuclear transport factor 2 family protein, Streptomyces cattleya IF95_RS0115800 149 - - - protein (WP_014627231.1); 90/94 IF95_RS0115805 265 thioesterase thioesterase, Streptomyces cattleya (WP_014140907.1); 90/94 - - - IF95_RS0115810 408 cytochrome P450 cytochrome P450, Streptomyces sp. E5N91 SAI-083 (WP_123627594.1); 90/94 - - - helix-turn-helix transcriptional regulator, Streptomyces cattleya IF95_RS0115815 924 LuxR family transcriptional regulator - - - (WP_014140903.1); 89/93 crotonyl-CoA carboxylase/reductase, Streptomyces olivaceus IF95_RS0115820 454 crotonyl-CoA carboxylase/reductase - - - (WP_070390081.1); 96/97 hypothetical protein EDC84_6806, Streptomyces sp. E5N91 SAI-083 IF95_RS0115825 145 hypothetical protein - - - (ROO97928.1); 89/91 SDR family NAD(P)-dependent IF95_RS0115830 277 SDR family oxidoreductase, Streptomyces cattleya (WP_014140897.1);95/97 - - - oxidoreductase LLM class flavin-dependent LLM class flavin-dependent oxidoreductase, Streptomyces cattleya IF95_RS0115835 393 - - - oxidoreductase (WP_014140896.1); 94/96

137 Table S83. Predicted functions of ORFs in potential abyssomicin BGC from Actinocrispum wychmicini DSM 45934 (NZ_SLWS01000002).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog TetR family transcriptional TetR/AcrR family transcriptional regulator, Corallococcus sp. H22C18031201 EV192_RS10885 196 - AbsC2 - regulator (WP_120202919.1); 55/70 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Streptomyces formicae EV192_RS10890 492 AbyD AbsD AbmD transporter permease subunit (WP_098241238.1); 54/72 EV192_RS10895 444 FAD-dependent oxidoreductase monooxygenase, Frankia canadensis (WP_101832044.1); 54/65 - - - EV192_RS10900 396 cytochrome P450 cytochrome P450, Actinoplanes sp. N902-109 (WP_015620517.1); 51/70 AbyX/AbyV AbsV/AbsX AbmV MsnO8 family LLM class luciferase family oxidoreductase, group 1, Kibdelosporangium aridum EV192_RS10905 346 AbyE AbsE AbmE1 oxidoreductase (SMD20744.1); 64/76 dipeptide ABC transporter ATP- EV192_RS10910 534 AbmF4, Streptomyces koyangensis (AVI57415.1); 63/77 AbyF4 AbsF4 AbmF4 binding protein ABC transporter permease EV192_RS10915 282 ABC transporter permease, Actinomadura macra (WP_067456459.1); 64/76 AbyF3 AbsF3 AbmF3 subunit ABC transporter permease EV192_RS10920 325 ABC transporter permease, Actinomadura sp. 5-2 (WP_103566287.1); 66/79 AbyF2 AbsF2 AbmF2 subunit ABC transporter substrate- ABC transporter substrate-binding protein, Streptomyces formicae EV192_RS10925 587 AbyF1 AbsF1 AbmF1 binding protein (WP_098241233.1); 56/69 EV192_RS10930 264 SDR family oxidoreductase SDR family oxidoreductase, Actinomadura macra (WP_084265034.1); 66/76 - - - EV192_RS10935 138 hypothetical protein hypothetical protein, Actinomadura meyerae (WP_089329757.1); 53/70 - - - 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Streptomyces sp. E5N91 SAI-083 EV192_RS10940 312 AbyA1 AbsA1 AbmA1 family protein (WP_123627122.1); 66/81 EV192_RS10945 75 acyl carrier protein acyl carrier protein, Frankia sp. ACN1ag (KQC35070.1); 66/82 AbyA3 AbsA3 AbmA3 EV192_RS10950 216 acyltransferase acyltransferase, Streptomyces armeniacus (AXK32424.1); 69/81 AbyA4 AbsA4 AbmA4 alpha/beta hydrolase, Streptomyces sp. NRRL F-525 (WP_033287161.1); EV192_RS10955 356 alpha/beta hydrolase AbyA5 AbsA5 AbmA5 62/74 EV192_RS10960 4517 PKS I QmnA1, Amycolatopsis orientalis (AFI57005.1); 56/66 PKS I PKS I PKS I EV192_RS10965 2460 PKS I type-I PKS, Streptomyces noursei (PNE39797.1); 53/65 PKS I PKS I PKS I SDR family NAD(P)-dependent oxidoreductase, Streptomyces lydicus EV192_RS10970 861 PKS I PKS I PKS I PKS I (WP_129293092.1); 57/69 type I polyketide synthase, Allokutzneria sp. NRRL B-24872 EV192_RS10975 240 PKS I PKS I PKS I PKS I (WP_086824400.1); 60/68 polyketide synthase, partial, Streptomyces rubellomurinus subsp. indigoferus EV192_RS10980 292 PKS I PKS I PKS I PKS I (KJS52288.1); 65/74 polyketide synthase, partial, Streptomyces hygroscopicus subsp. EV192_RS10985 132 PKS I PKS I PKS I PKS I hygroscopicus (BAH67173.1); 65/74 EV192_RS10990 325 PKS I ChlA1, Streptomyces antibioticus (AAZ77693.1); 60/74 PKS I PKS I PKS I type I polyketide synthase, Streptomyces sp. NBRC 109436 EV192_RS10995 1266 PKS I PKS I PKS I PKS I (WP_079150001.1); 57/67

138 EV192_RS11000 314 activator protein activator protein, Kutzneria buriramensis (WP_116181646.1); 69/78 AbyI/AbyR - AbmI

139 Table S84. Predicted functions of ORFs in potential chlorothricin BGC from Actinocrispum wychmicini DSM 45934 (NZ_SLWS01000003).

Size Aby Abs Abm ORF Proposed function Closest homolog, host (protein ID); Identity/Similarity (%) (aa) homolog homolog homolog EV192_RS1614 ketoacyl-ACP synthase III, Streptomyces diastatochromogenes (WP_094222628.1); 338 beta-ketoacyl-ACP synthase 3 - - - 0 71/82 EV192_RS1614 3-hydroxybutyryl-CoA 3-hydroxybutyryl-CoA dehydrogenase, Streptomyces sp. NRRL B-3648 291 - - - 5 dehydrogenase (WP_053711641.1); 68/79 EV192_RS1615 acyl-CoA carboxylase subunit acyl-CoA carboxylase subunit beta, Amycolatopsis orientalis (WP_043836795.1); 520 - - - 0 beta 83/90 EV192_RS1615 345 aldo/keto reductase aldo/keto reductase, Streptomyces sp. DSM 15324 (WP_079079511.1); 76/84 - - - 5 EV192_RS1616 462 NDP-hexose 2,3-dehydratase NDP-hexose 2,3-dehydratase, Streptomyces sp. Ru73 (WP_103830972.1); 70/81 - - - 0 EV192_RS1616 404 cytochrome P450 cytochrome P450, Actinomadura pelletieri (WP_121438133.1); 61/71 - - - 5 EV192_RS1617 79 hypothetical protein hypothetical protein, Stackebrandtia nassauensis (WP_013019899.1); 69/80 - - - 0 EV192_RS1617 158 hypothetical protein Clp protease, Nakamurella sp. 12Sc4-1 (WP_111766871.1); 45/60 - - - 5 EV192_RS1618 DHA2 family efflux MFS DHA2 family efflux MFS transporter permease subunit, Plantactinospora sp. KBS50 490 - - - 0 transporter permease subunit (WP_095565847.1); 52/66 EV192_RS1618 LuxR family transcriptional LuxR family transcriptional regulator, Streptomyces armeniacus (AXK33357.1); 927 - - - 5 regulator 45/58 EV192_RS1619 354 alpha/beta hydrolase alpha/beta hydrolase, Actinomadura pelletieri (WP_121438111.1); 65/77 - - - 0 EV192_RS1619 256 acyltransferase acyltransferase, Actinomadura pelletieri (WP_121438112.1); 71/81 - - - 5 EV192_RS1620 76 acyl carrier protein acyl carrier protein, Streptomyces armeniacus (AXK32426.1); 60/80 - - - 0 EV192_RS1620 634 HAD-IIIC family phosphatase HAD-IIIC family phosphatase, Actinomadura pelletieri (WP_121438114.1); 63/76 - - - 5 EV192_RS1621 3-oxoacyl-ACP synthase III 3-oxoacyl-ACP synthase III family protein, Actinomadura pelletieri 343 - - - 0 family protein (WP_121438115.1); 76/87 EV192_RS1621 474 monooxygenase hypothetical protein, Actinomadura pelletieri (WP_121438116.1); 62/71 - - - 5 EV192_RS1622 acyltransferase domain-containing protein, Actinomadura pelletieri 1355 PKS I - - - 0 (WP_121438117.1); 55/64 EV192_RS1622 SDR family NAD(P)-dependent oxidoreductase, Actinomadura pelletieri 2904 PKS I - - - 5 (WP_121438118.1); 63/74 EV192_RS1623 SDR family NAD(P)-dependent oxidoreductase, Actinomadura pelletieri 1074 PKS I - - - 0 (WP_121438118.1); 70/79 EV192_RS1623 Phosphopantetheine attachment site, partial, Micromonospora matsumotoense 239 PKS I - - - 5 (SCF50095.1); 53/65 EV192_RS1624 SDR family NAD(P)-dependent oxidoreductase, Actinomadura pelletieri 355 PKS I - - - 0 (WP_121438352.1); 60/70

140 EV192_RS1624 SDR family NAD(P)-dependent oxidoreductase, Streptomyces sp. 11-1-2 759 PKS I - - - 5 (WP_119988543.1); 65/76 EV192_RS1625 1261 PKS I modular polyketide synthase, Streptomyces sp. RK95-74 (BAW35613.1); 52/64 - - - 0 EV192_RS1625 680 PKS I ChlA3, Streptomyces antibioticus (AAZ77696.1); 65/76 - - - 5 EV192_RS1626 SDR family NAD(P)-dependent oxidoreductase, Streptomyces alboflavus 301 PKS I - - - 0 (WP_125262907.1); 65/73 EV192_RS1626 SDR family NAD(P)-dependent oxidoreductase, Actinomadura pelletieri 340 PKS I - - - 5 (WP_121438119.1); 57/69 EV192_RS1627 130 PKS I QmnA3, Amycolatopsis orientalis (AFI57007.1); 63/75 - - - 0 EV192_RS1627 SDR family NAD(P)-dependent oxidoreductase, Actinomadura pelletieri 245 PKS I - - - 5 (WP_121438119.1); 83/89 EV192_RS1628 SDR family NAD(P)-dependent oxidoreductase, partial, Streptomyces sp. AM-2504 159 PKS I - - - 0 (WP_131124269.1); 58/68 EV192_RS1628 KR domain-containing protein, partial, Streptomyces sp. MnatMP-M27 314 PKS I - - - 5 (SCG13790.1); 65/74 EV192_RS1629 SDR family NAD(P)-dependent oxidoreductase, Actinomadura pelletieri 899 PKS I - - - 0 (WP_121438119.1); 62/73 EV192_RS1629 SDR family NAD(P)-dependent oxidoreductase, Actinomadura pelletieri 1566 PKS I - - - 5 (WP_121438120.1); 57/67 EV192_RS1630 4361 PKS I Ann4, Streptomyces calvus (AGY30676.1); 52/63 - - - 0 EV192_RS1630 386 acyl-CoA dehydrogenase acyl-CoA dehydrogenase, Saccharomonospora saliphila (WP_019815635.1); 69/80 - - - 5 EV192_RS1631 DUF1205 domain-containing DUF1205 domain-containing protein, Actinomadura pelletieri (WP_121438132.1); 401 - - - 0 protein 48/65 aminotransferase class I/II-fold EV192_RS1631 aminotransferase class I/II-fold pyridoxal phosphate-dependent enzyme, 384 pyridoxal phosphate-dependent - - - 5 Amycolatopsis japonica (WP_051972467.1); 62/75 enzyme EV192_RS1632 347 3-oxoacyl-ACP synthase 3-oxoacyl-ACP synthase, Actinomadura pelletieri (WP_121438128.1); 74/84 - - - 0 EV192_RS1632 acyltransferase domain- acyltransferase domain-containing protein, Actinomadura pelletieri 1724 - - - 5 containing protein (WP_121438127.1); 61/72 EV192_RS1633 NAD(P)/FAD-dependent oxidoreductase, Actinomadura pelletieri 448 FAD-dependent oxidoreductase - - - 0 (WP_121438126.1); 79/88 EV192_RS1633 88 acyl carrier protein ChlB2, Streptomyces antibioticus (AAZ77675.1); 55/72 - - - 5 EV192_RS1634 349 3-oxoacyl-ACP synthase 3-oxoacyl-ACP synthase, Micromonospora haikouensis (WP_091284724.1); 58/71 - - - 0 EV192_RS1634 261 alpha/beta fold hydrolase thioesterase, Streptomyces aurantiacus (WP_055507818.1); 59/72 - - - 5 EV192_RS1635 256 activator protein activator protein, Actinomadura sp. LMG 30035 (WP_131738462.1); 67/80 - - - 0 EV192_RS1635 182 Diels-Alderase hypothetical protein, Actinomadura pelletieri (WP_121438130.1); 50/62 AbyU AbsU AbmU 5

141 EV192_RS1636 344 methyltransferase methyltransferase family protein, Actinocrispum wychmicini (TCO60814.1); 99/100 - - - 0

142 Table S85. Predicted genomic islands nearby the abyssomicin BGC from Actinokineospora auranticolor YU 961-1 (PTIX01000011.1).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number PPK66181. 183112 188952 5840 IslandPath-DIMOB CLV40_111145 182417 183133 1 hypothetical protein 1 PPK66182. 183112 188952 5840 IslandPath-DIMOB CLV40_111146 183112 183891 -1 DDE superfamily endonuclease 1 PPK66183. 183112 188952 5840 IslandPath-DIMOB CLV40_111147 184081 184374 1 transposase 1 PPK66184. 183112 188952 5840 IslandPath-DIMOB CLV40_111148 184371 185255 1 transposase InsO family protein 1 1 PPK66185. 183112 188952 5840 IslandPath-DIMOB CLV40_111149 185345 185479 -1 hypothetical protein 1 PPK66186. 183112 188952 5840 IslandPath-DIMOB CLV40_111150 186133 187383 -1 deoxyribonuclease NucA/NucB 1 PPK66187. 183112 188952 5840 IslandPath-DIMOB CLV40_111151 187781 188074 1 transposase-like protein 1 PPK66188. 183112 188952 5840 IslandPath-DIMOB CLV40_111152 188134 188952 1 putative transposase 1

143 Table S86. Predicted genomic islands in the abyssomicin BGC from Frankia sp. EAN1pec (CP000820.1).

Island Island Island end Length Method Gene name Locus Gene start Gene end Strand Product number start 1 IslandPath- 4037626 4083572 45946 WP_020460948.1 FRANEAN1_RS16505 4036943 4037629 1 hydrogenase DIMOB IslandPath- 4037626 4083572 45946 WP_020460949.1 FRANEAN1_RS16510 4037626 4038201 1 HybD peptidase DIMOB IslandPath- 4037626 4083572 45946 WP_020460950.1 FRANEAN1_RS16515 4038194 4038514 1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 WP_041254273.1 FRANEAN1_RS16520 4038597 4039307 1 transposase DIMOB IslandPath- 4037626 4083572 45946 FRANEAN1_RS16525 4039538 4040605 -1 integrase DIMOB IslandPath- 4037626 4083572 45946 FRANEAN1_RS16530 4041090 4042106 1 transposase DIMOB IslandPath- group II intron reverse 4037626 4083572 45946 WP_041254274.1 FRANEAN1_RS16535 4042771 4044030 1 DIMOB transcriptase/maturase IslandPath- 4037626 4083572 45946 WP_041254276.1 FRANEAN1_RS16540 4044349 4045413 -1 integrase DIMOB IslandPath- 4037626 4083572 45946 WP_020460958.1 FRANEAN1_RS16545 4045559 4046086 1 transposase DIMOB IslandPath- 4037626 4083572 45946 WP_020460959.1 FRANEAN1_RS16550 4046250 4047026 1 endonuclease DIMOB IslandPath- 4037626 4083572 45946 WP_020460962.1 FRANEAN1_RS16555 4049067 4049702 1 transposase DIMOB IslandPath- 4037626 4083572 45946 DIMOB and WP_020460963.1 FRANEAN1_RS16560 4049877 4050305 1 hypothetical protein SIGI-HMM IslandPath- 4037626 4083572 45946 DIMOB and WP_020460964.1 FRANEAN1_RS16565 4050568 4051017 -1 hypothetical protein SIGI-HMM IslandPath- 4037626 4083572 45946 DIMOB and WP_020460965.1 FRANEAN1_RS16570 4051014 4052702 -1 long-chain-fatty-acid--CoA ligase SIGI-HMM IslandPath- 4037626 4083572 45946 DIMOB and WP_020460966.1 FRANEAN1_RS16575 4053138 4054232 1 transposase SIGI-HMM IslandPath- 4037626 4083572 45946 DIMOB and WP_041254279.1 FRANEAN1_RS16580 4056659 4056949 -1 hypothetical protein SIGI-HMM IslandPath- 4037626 4083572 45946 DIMOB and WP_041254281.1 FRANEAN1_RS16585 4057354 4057620 -1 hypothetical protein SIGI-HMM IslandPath- 4037626 4083572 45946 WP_020460972.1 FRANEAN1_RS16590 4059514 4060779 1 transposase DIMOB 4037626 4083572 45946 IslandPath- WP_049795687.1 FRANEAN1_RS16595 4060884 4061411 -1 hypothetical protein

144 DIMOB IslandPath- 4037626 4083572 45946 WP_020460974.1 FRANEAN1_RS16600 4061557 4061805 1 transposase DIMOB IslandPath- 4037626 4083572 45946 WP_020460977.1 FRANEAN1_RS16610 4063942 4065843 1 hypothetical protein DIMOB IslandPath- peptidase C15 pyroglutamyl 4037626 4083572 45946 WP_020460978.1 FRANEAN1_RS16615 4065997 4066383 1 DIMOB peptidase I IslandPath- 4037626 4083572 45946 WP_020460979.1 FRANEAN1_RS16620 4066403 4068013 1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 WP_020458361.1 FRANEAN1_RS16625 4068230 4069618 -1 transposase DIMOB IslandPath- 4037626 4083572 45946 FRANEAN1_RS16630 4069765 4070127 -1 transposase DIMOB IslandPath- 4037626 4083572 45946 WP_020460981.1 FRANEAN1_RS16635 4070259 4070747 -1 transposase DIMOB IslandPath- 4037626 4083572 45946 WP_049795688.1 FRANEAN1_RS16640 4070863 4071195 1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 WP_020460983.1 FRANEAN1_RS16645 4071324 4073876 -1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 FRANEAN1_RS16650 4074150 4075388 1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 WP_041254282.1 FRANEAN1_RS16655 4076180 4076416 1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 WP_020460987.1 FRANEAN1_RS16660 4076633 4077709 1 recombinase DIMOB IslandPath- 4037626 4083572 45946 WP_020460988.1 FRANEAN1_RS16665 4077805 4078125 1 XRE family transcriptional regulator DIMOB IslandPath- 4037626 4083572 45946 WP_020460989.1 FRANEAN1_RS16670 4078128 4079762 1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 WP_049795689.1 FRANEAN1_RS16675 4080154 4080387 -1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 WP_020460992.1 FRANEAN1_RS37180 4081077 4081268 1 hypothetical protein DIMOB IslandPath- 4037626 4083572 45946 WP_020460993.1 FRANEAN1_RS16685 4081417 4081926 1 molecular chaperone DnaJ DIMOB IslandPath- 4037626 4083572 45946 FRANEAN1_RS16690 4082160 4083245 1 HNH endonuclease DIMOB IslandPath- 4037626 4083572 45946 WP_020460995.1 FRANEAN1_RS16695 4083267 4083572 -1 hypothetical protein DIMOB IslandPath- 4049877 4057620 7743 WP_020460963.1 FRANEAN1_RS16560 4049877 4050305 1 hypothetical protein DIMOB IslandPath- 4049877 4057620 7743 WP_020460964.1 FRANEAN1_RS16565 4050568 4051017 -1 hypothetical protein DIMOB IslandPath- 4049877 4057620 7743 WP_020460965.1 FRANEAN1_RS16570 4051014 4052702 -1 long-chain-fatty-acid--CoA ligase DIMOB 4049877 4057620 7743 IslandPath- WP_020460966.1 FRANEAN1_RS16575 4053138 4054232 1 transposase DIMOB

145 IslandPath- 4049877 4057620 7743 WP_041254279.1 FRANEAN1_RS16580 4056659 4056949 -1 hypothetical protein DIMOB IslandPath- 4049877 4057620 7743 WP_041254281.1 FRANEAN1_RS16585 4057354 4057620 -1 hypothetical protein DIMOB 5- IslandPath- 4162485 4178361 15876 WP_020461039.1 FRANEAN1_RS16930 4162485 4162649 1 methyltetrahydropteroyltriglutamate- DIMOB - homocysteine methyltransferase IslandPath- 4162485 4178361 15876 WP_020461040.1 FRANEAN1_RS16935 4162734 4163462 -1 hypothetical protein DIMOB IslandPath- 4162485 4178361 15876 WP_020461041.1 FRANEAN1_RS16940 4163485 4163964 1 biotin carboxylase DIMOB IslandPath- 4162485 4178361 15876 WP_049795955.1 FRANEAN1_RS16945 4164164 4165327 -1 transposase DIMOB IslandPath- 4162485 4178361 15876 WP_020461044.1 FRANEAN1_RS16950 4165962 4166978 1 hypothetical protein DIMOB IslandPath- 4162485 4178361 15876 WP_020461045.1 FRANEAN1_RS16955 4166975 4167850 1 N-acetyltransferase GCN5 DIMOB IslandPath- 4162485 4178361 15876 WP_020461046.1 FRANEAN1_RS37185 4167903 4168769 -1 restriction endonuclease DIMOB IslandPath- 4162485 4178361 15876 WP_020461047.1 FRANEAN1_RS16965 4169026 4169463 1 hypothetical protein DIMOB IslandPath- 4162485 4178361 15876 WP_049795690.1 FRANEAN1_RS37190 4169505 4169693 -1 hypothetical protein 2 DIMOB IslandPath- 4162485 4178361 15876 WP_049795691.1 FRANEAN1_RS37195 4169904 4170146 1 hypothetical protein DIMOB IslandPath- 4162485 4178361 15876 WP_020461048.1 FRANEAN1_RS16975 4170166 4171362 -1 transposase DIMOB IslandPath- 4162485 4178361 15876 WP_020461049.1 FRANEAN1_RS16980 4171738 4172307 1 ATPase AAA DIMOB IslandPath- 4162485 4178361 15876 WP_020461050.1 FRANEAN1_RS16985 4172548 4173339 1 alpha-hydroxy acid dehydrogenase DIMOB IslandPath- 4162485 4178361 15876 WP_041254292.1 FRANEAN1_RS16990 4173460 4173927 -1 polyketide cyclase DIMOB IslandPath- 4162485 4178361 15876 WP_020461052.1 FRANEAN1_RS16995 4174246 4175001 1 hypothetical protein DIMOB IslandPath- 4162485 4178361 15876 WP_020461053.1 FRANEAN1_RS17000 4175403 4175837 -1 N-acetyltransferase GCN5 DIMOB IslandPath- 4162485 4178361 15876 WP_020461054.1 FRANEAN1_RS17005 4176055 4177173 -1 type 11 methyltransferase DIMOB IslandPath- 4162485 4178361 15876 WP_041254293.1 FRANEAN1_RS17010 4177531 4178361 -1 aminoglycoside phosphotransferase DIMOB

146 Table S87. Predicted genomic islands nearby the abyssomicin BGC from Herbidospora sakaeratensis NBRC 102641 (NZ_BBXC01000032).

Island Stran Island start Island end Length Method Gene name Locus Gene start Gene end Product number d 56040 60649 4609 SIGI-HMM WP_062343049.1 AW271_RS37545 56040 56351 1 hypothetical protein helix-turn-helix domain-containing 56040 60649 4609 SIGI-HMM WP_062343051.1 AW271_RS37550 56430 57275 -1 protein SDR family NAD(P)-dependent 56040 60649 4609 SIGI-HMM WP_062343072.1 AW271_RS37555 57419 58267 1 oxidoreductase 1 56040 60649 4609 SIGI-HMM WP_062343053.1 AW271_RS37560 58577 59458 -1 haloalkane dehalogenase 4-oxalocrotonate tautomerase 56040 60649 4609 SIGI-HMM WP_062343055.1 AW271_RS37565 59571 59795 -1 family protein helix-turn-helix transcriptional 56040 60649 4609 SIGI-HMM WP_062343058.1 AW271_RS37570 60152 60649 1 regulator

147 Table S88. Predicted genomic islands in the potential BGC from Streptomyces cattleya DSM 46488 (NC_017586.1).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number 1 118712 149510 30798 IslandPath-DIMOB WP_014140884.1 SCATT_RS00500 118712 119890 1 hypothetical protein 118712 149510 30798 IslandPath-DIMOB WP_014627221.1 SCATT_RS00505 120052 121530 1 hypothetical protein 118712 149510 30798 IslandPath-DIMOB WP_014140886.1 SCATT_RS00510 121668 122774 1 hypothetical protein GNAT family N- 118712 149510 30798 IslandPath-DIMOB WP_014140887.1 SCATT_RS00515 122863 123426 1 acetyltransferase 118712 149510 30798 IslandPath-DIMOB WP_014140888.1 SCATT_RS00520 123516 124982 1 phosphohydrolase DUF72 domain-containing 118712 149510 30798 IslandPath-DIMOB WP_014140889.1 SCATT_RS00525 125072 125857 1 protein D-alanyl-D-alanine 118712 149510 30798 IslandPath-DIMOB WP_014140890.1 SCATT_RS00530 125974 126939 1 carboxypeptidase lytic transglycosylase 118712 149510 30798 IslandPath-DIMOB WP_014140891.1 SCATT_RS00535 127454 127849 1 domain-containing protein SpoIIE family protein 118712 149510 30798 IslandPath-DIMOB WP_014140892.1 SCATT_RS00540 128044 130809 1 phosphatase DUF1360 domain-containing 118712 149510 30798 IslandPath-DIMOB WP_086010104.1 SCATT_RS00545 130879 131373 -1 protein 118712 149510 30798 IslandPath-DIMOB WP_014140894.1 SCATT_RS00550 131632 133032 1 dihydrolipoyl dehydrogenase 118712 149510 30798 IslandPath-DIMOB WP_014140895.1 SCATT_RS00555 134176 134448 1 hypothetical protein LLM class flavin-dependent 118712 149510 30798 IslandPath-DIMOB WP_014140896.1 SCATT_RS00560 134445 135626 1 oxidoreductase 118712 149510 30798 IslandPath-DIMOB WP_014140897.1 SCATT_RS00565 135869 136702 1 SDR family oxidoreductase 118712 149510 30798 IslandPath-DIMOB WP_014140898.1 SCATT_RS35820 136793 137098 1 hypothetical protein crotonyl-CoA 118712 149510 30798 IslandPath-DIMOB WP_014140899.1 SCATT_RS00570 137239 138603 1 carboxylase/reductase 118712 149510 30798 IslandPath-DIMOB WP_014140901.1 SCATT_RS35620 139045 139374 1 transposase helix-turn-helix transcriptional 118712 149510 30798 IslandPath-DIMOB WP_014140903.1 SCATT_RS00580 139609 142386 1 regulator 118712 149510 30798 IslandPath-DIMOB WP_014627227.1 SCATT_RS00585 142847 143074 1 hypothetical protein 118712 149510 30798 IslandPath-DIMOB WP_014627229.1 SCATT_RS00590 143554 144780 -1 cytochrome P450 118712 149510 30798 IslandPath-DIMOB WP_014140907.1 SCATT_RS00595 144777 145796 -1 thioesterase nuclear transport factor 2 118712 149510 30798 IslandPath-DIMOB WP_014627231.1 SCATT_RS00600 145951 146427 -1 family protein NAD(P)-dependent 118712 149510 30798 IslandPath-DIMOB WP_014140909.1 SCATT_RS00605 146521 147363 -1 oxidoreductase 118712 149510 30798 IslandPath-DIMOB WP_014140910.1 SCATT_RS00610 147412 147834 -1 hypothetical protein 118712 149510 30798 IslandPath-DIMOB WP_014627233.1 SCATT_RS00615 147862 148263 -1 nuclear transport factor 2 family protein

148 cytochrome P450 118712 149510 30798 IslandPath-DIMOB WP_014140912.1 SCATT_RS00620 148260 149510 -1

149 Table S89. Predicted genomic islands nearby AbyU homolog from Streptomyces armeniacus ATCC 15676 (CP031320.1).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number 7286945 7297167 10222 IslandPath-DIMOB AXK36495.1 DVA86_31895 7285777 7286970 1 DUF1205 domain-containing protein 7286945 7297167 10222 IslandPath-DIMOB AXK36496.1 DVA86_31900 7286945 7287814 1 hypothetical protein 7286945 7297167 10222 IslandPath-DIMOB AXK36497.1 DVA86_31905 7288161 7288919 1 phage Gp37/Gp68 family protein 7286945 7297167 10222 IslandPath-DIMOB AXK36498.1 DVA86_31910 7288959 7290155 -1 hypothetical protein 1 7286945 7297167 10222 IslandPath-DIMOB AXK36499.1 DVA86_31915 7290475 7290762 1 hypothetical protein 7286945 7297167 10222 IslandPath-DIMOB AXK36500.1 DVA86_31920 7290944 7293595 -1 ATP/GTP-binding protein 7286945 7297167 10222 IslandPath-DIMOB AXK37815.1 DVA86_31925 7293886 7294101 1 hypothetical protein 7286945 7297167 10222 IslandPath-DIMOB AXK37814.1 DVA86_31930 7294077 7295885 -1 ATP/GTP-binding protein 7286945 7297167 10222 IslandPath-DIMOB AXK36501.1 DVA86_31935 7296034 7297167 1 Fic family protein

150 Table S90. Predicted genomic islands in potential BGC from Streptomyces iranensis DSM 41954 (NZ_LK022848).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number 11040571 11048595 8024 IslandPick WP_044580002.1 SIRAN_RS44125 11037896 11040580 1 glucan biosynthesis protein 11040571 11048595 8024 IslandPick WP_078957437.1 SIRAN_RS51845 11040877 11041341 -1 nuclear transport factor 2 family protein 11040571 11048595 8024 IslandPick WP_078957138.1 SIRAN_RS51850 11041468 11042301 -1 NAD(P)-dependent oxidoreductase 1 11040571 11048595 8024 IslandPick WP_078957139.1 SIRAN_RS51855 11042451 11042873 -1 hypothetical protein 11040571 11048595 8024 IslandPick WP_078957140.1 SIRAN_RS44130 11042902 11043261 -1 nuclear transport factor 2 family protein 11040571 11048595 8024 IslandPick WP_044580004.1 SIRAN_RS44135 11043300 11044553 -1 cytochrome P450 11040571 11048595 8024 IslandPick WP_044580005.1 SIRAN_RS44140 11044641 11063105 -1 type I polyketide synthase 11062737 11066838 4101 IslandPick WP_044580005.1 SIRAN_RS44140 11044641 11063105 -1 type I polyketide synthase 2 11062737 11066838 4101 IslandPick SIRAN_RS44145 11063102 11074674 -1 3-ketoacyl-ACP synthase 11072390 11078862 6472 IslandPick SIRAN_RS44145 11063102 11074674 -1 3-ketoacyl-ACP synthase 11072390 11078862 6472 IslandPick WP_078957141.1 SIRAN_RS51860 11074773 11076665 -1 type I polyketide synthase

3 pyridoxamine 5'-phosphate oxidase 11072390 11078862 6472 IslandPick WP_044580008.1 SIRAN_RS44165 11076907 11077464 -1 family protein

11072390 11078862 6472 IslandPick WP_044580009.1 SIRAN_RS44170 11077848 11089649 1 type I polyketide synthase 11085080 11090496 5416 IslandPick WP_044580009.1 SIRAN_RS44170 11077848 11089649 1 type I polyketide synthase 4 11085080 11090496 5416 IslandPick WP_044580010.1 SIRAN_RS44175 11089703 11093776 1 type I polyketide synthase 11091079 11102579 11500 IslandPick WP_044580010.1 SIRAN_RS44175 11089703 11093776 1 type I polyketide synthase 11091079 11102579 11500 IslandPick WP_078957142.1 SIRAN_RS51865 11093717 11094226 -1 hypothetical protein 11091079 11102579 11500 IslandPick WP_044580011.1 SIRAN_RS44180 11094468 11095301 -1 SDR family oxidoreductase LLM class flavin-dependent 11091079 11102579 11500 IslandPick WP_044580012.1 SIRAN_RS44185 11095683 11096864 1 oxidoreductase 5 11091079 11102579 11500 IslandPick SIRAN_RS44190 11096920 11097126 1 thioesterase 11091079 11102579 11500 IslandPick WP_078957143.1 SIRAN_RS44195 11097123 11098349 1 cytochrome P450 11091079 11102579 11500 IslandPick SIRAN_RS51870 11098657 11099193 -1 hypothetical protein 11091079 11102579 11500 IslandPick WP_044580016.1 SIRAN_RS44205 11099197 11101998 -1 helix-turn-helix transcriptional regulator 11091079 11102579 11500 IslandPick WP_107073432.1 SIRAN_RS53370 11102469 11102720 1 hypothetical protein

151 Table S91. Predicted genomic islands nearby AbyU homolog from Streptomyces caatingaensis CMAA 1322 (NZ_LFXA01000017).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number 1 IslandPath-DIMOB 223990 272192 48202 WP_049718312.1 AC230_RS23380 223990 225192 -1 beta-ketoacyl-ACP synthase II TetR/AcrR family transcriptional 223990 272192 48202 IslandPath-DIMOB WP_049718313.1 AC230_RS23385 225404 226003 1 regulator 223990 272192 48202 IslandPath-DIMOB WP_049718314.1 AC230_RS23390 225972 226367 -1 hypothetical protein

zinc-dependent alcohol 223990 272192 48202 IslandPath-DIMOB WP_049718315.1 AC230_RS23395 226575 227609 1 dehydrogenase family protein DUF4188 domain-containing 223990 272192 48202 IslandPath-DIMOB WP_078871521.1 AC230_RS31430 227616 228092 -1 protein DUF1211 domain-containing 223990 272192 48202 IslandPath-DIMOB WP_049718316.1 AC230_RS23410 228394 229050 -1 protein N-acetyl-gamma-glutamyl- 223990 272192 48202 IslandPath-DIMOB WP_049718317.1 AC230_RS23415 229187 230215 1 phosphate reductase

bifunctional glutamate N- 223990 272192 48202 IslandPath-DIMOB WP_049718318.1 AC230_RS23420 230212 231363 1 acetyltransferase/amino-acid acetyltransferase ArgJ

223990 272192 48202 IslandPath-DIMOB WP_049718319.1 AC230_RS23425 231360 232268 1 acetylglutamate kinase 223990 272192 48202 IslandPath-DIMOB WP_049718320.1 AC230_RS23430 232265 233452 1 acetylornithine transaminase 223990 272192 48202 IslandPath-DIMOB WP_049718321.1 AC230_RS23435 233512 234057 1 arginine repressor 223990 272192 48202 IslandPath-DIMOB WP_049718322.1 AC230_RS23440 234137 235183 1 hypothetical protein DUF397 domain-containing 223990 272192 48202 IslandPath-DIMOB WP_078871522.1 AC230_RS31435 235122 235313 -1 protein helix-turn-helix domain-containing 223990 272192 48202 IslandPath-DIMOB WP_078871523.1 AC230_RS23445 235310 236563 -1 protein 223990 272192 48202 IslandPath-DIMOB WP_078871524.1 AC230_RS23455 236681 237448 1 signal peptidase I 223990 272192 48202 IslandPath-DIMOB WP_049718325.1 AC230_RS23460 238453 238845 -1 hypothetical protein 223990 272192 48202 IslandPath-DIMOB WP_049718326.1 AC230_RS23465 238903 239382 -1 IS5/IS1182 family transposase 223990 272192 48202 IslandPath-DIMOB WP_049718327.1 AC230_RS23470 239688 240203 -1 DUF2247 family protein 223990 272192 48202 IslandPath-DIMOB WP_078871525.1 AC230_RS23475 240220 243255 -1 hypothetical protein 223990 272192 48202 IslandPath-DIMOB WP_049718328.1 AC230_RS23480 243221 243604 1 hypothetical protein 223990 272192 48202 IslandPath-DIMOB AC230_RS23485 243611 243889 -1 GNAT family N-acetyltransferase 223990 272192 48202 IslandPath-DIMOB WP_049718329.1 AC230_RS23490 244234 244626 -1 hypothetical protein 223990 272192 48202 IslandPath-DIMOB WP_078871526.1 AC230_RS23495 244648 251268 -1 sugar-binding protein 223990 272192 48202 IslandPath-DIMOB WP_078871587.1 AC230_RS23500 251663 255541 -1 LamG domain-containing protein

152 MarR family transcriptional 223990 272192 48202 IslandPath-DIMOB WP_049718331.1 AC230_RS23505 256202 256687 1 regulator respiratory nitrate reductase 223990 272192 48202 IslandPath-DIMOB WP_049718332.1 AC230_RS23510 256705 257391 -1 subunit gamma nitrate reductase molybdenum 223990 272192 48202 IslandPath-DIMOB WP_049718333.1 AC230_RS23515 257408 257986 -1 cofactor assembly chaperone

223990 272192 48202 IslandPath-DIMOB WP_078871588.1 AC230_RS23520 257983 259566 -1 nitrate reductase subunit beta 223990 272192 48202 IslandPath-DIMOB AC230_RS23525 259577 263262 -1 nitrate reductase subunit alpha 223990 272192 48202 IslandPath-DIMOB WP_049718334.1 AC230_RS23530 264241 266856 1 M4 family peptidase DegT/DnrJ/EryC1/StrS family 223990 272192 48202 IslandPath-DIMOB WP_049718335.1 AC230_RS23535 267031 268311 1 aminotransferase 223990 272192 48202 IslandPath-DIMOB WP_053161355.1 AC230_RS30460 268308 269315 1 hypothetical protein 223990 272192 48202 IslandPath-DIMOB WP_049718851.1 AC230_RS23545 269404 269637 1 hypothetical protein (2,3-dihydroxybenzoyl)adenylate 223990 272192 48202 IslandPath-DIMOB WP_049718336.1 AC230_RS23550 269634 271289 1 synthase 223990 272192 48202 IslandPath-DIMOB WP_049718337.1 AC230_RS23555 271401 272192 1 thioesterase 223990 272192 48202 IslandPath-DIMOB WP_049718338.1 AC230_RS23560 272189 273382 1 FAD-dependent oxidoreductase

153 Table S92. Predicted genomic islands in potential abyssomicin BGC from Streptomyces sp. SCA2-2 (NZ_PKMX01000004 and NZ_PKMX01000005).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number SIGI-HMM 3631 8735 5104 WP_129847664.1 C0L86_RS05545 2810 3634 -1 thioesterase

3631 8735 5104 SIGI-HMM WP_129847665.1 C0L86_RS05550 3631 4752 -1 alpha/beta hydrolase 3631 8735 5104 SIGI-HMM WP_129847666.1 C0L86_RS05555 4749 5591 -1 acyltransferase 1 3631 8735 5104 SIGI-HMM WP_129847667.1 C0L86_RS05560 5588 5815 -1 acyl carrier protein 3631 8735 5104 SIGI-HMM WP_129847668.1 C0L86_RS05565 5812 7698 -1 HAD-IIIC family phosphatase 3-oxoacyl-ACP synthase III family 3631 8735 5104 SIGI-HMM WP_129847669.1 C0L86_RS05570 7704 8735 -1 protein

154 Table S93. Predicted genomic islands in abyssomicin BGC from Streptomyces koyangensis SCSIO 5802 (MG243704).

Island Island start Island end Length Method Gene name Gene start Gene end Strand Product number 20783 25887 5104 SIGI-HMM AVI57426.1 20783 21814 1 AbmA1 20783 25887 5104 SIGI-HMM AVI57427.1 21820 23706 1 AbmA2 20783 25887 5104 SIGI-HMM AVI57428.1 23703 23930 1 AbmA3 1 20783 25887 5104 SIGI-HMM AVI57429.1 23927 24769 1 AbmA4 20783 25887 5104 SIGI-HMM AVI57430.1 24766 25887 1 AbmA5 20783 25887 5104 SIGI-HMM AVI57431.1 25884 26708 1 AbmT

155 Table S94. Predicted genomic islands in potential abyssomicin BGC from Streptomyces griseorubiginosus SAI-142 (NZ_RJKZ01000001.1).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number 6603102 6609081 5979 IslandPick WP_123763198.1 EDC83_RS30455 6598078 6604542 1 hypothetical protein 6603102 6609081 5979 IslandPick WP_123763199.1 EDC83_RS30460 6604545 6604937 1 hypothetical protein 6603102 6609081 5979 IslandPick WP_123765188.1 EDC83_RS30465 6604975 6605424 1 hypothetical protein 1 6603102 6609081 5979 IslandPick WP_123763200.1 EDC83_RS30470 6605491 6607155 1 hypothetical protein 6603102 6609081 5979 IslandPick WP_123763201.1 EDC83_RS30475 6607568 6608059 1 hypothetical protein 6603102 6609081 5979 IslandPick WP_123763202.1 EDC83_RS30480 6608210 6608725 1 hypothetical protein 6609385 6614640 5255 IslandPick WP_123763203.1 EDC83_RS30485 6609521 6612259 1 AAA family ATPase AfsR/SARP family transcriptional 6609385 6614640 5255 IslandPick WP_123763204.1 EDC83_RS30490 6612705 6613478 1 regulator 2 6609385 6614640 5255 IslandPick WP_123763205.1 EDC83_RS30495 6613527 6614363 -1 thioesterase 3-oxoacyl-ACP synthase III family 6609385 6614640 5255 IslandPick WP_123763206.1 EDC83_RS30500 6614604 6615635 1 protein acyltransferase domain-containing 6650159 6655065 4906 IslandPick WP_123763213.1 EDC83_RS30540 6646381 6651045 1 protein 6650159 6655065 4906 IslandPick WP_123763214.1 EDC83_RS30545 6650954 6652699 1 hypothetical protein 6650159 6655065 4906 IslandPick WP_123763215.1 EDC83_RS30550 6652748 6652933 1 hypothetical protein 3 6650159 6655065 4906 IslandPick WP_123763216.1 EDC83_RS30555 6653032 6654078 1 methyltransferase 6650159 6655065 4906 IslandPick WP_123763217.1 EDC83_RS30560 6654139 6654552 -1 hypothetical protein 6650159 6655065 4906 IslandPick WP_123763218.1 EDC83_RS30565 6654713 6654949 -1 ferredoxin 6650159 6655065 4906 IslandPick WP_123765190.1 EDC83_RS30570 6654943 6656052 -1 cytochrome P450

156 Table S95. Predicted genomic islands in potential tetronomycin BGC from Streptomyces olindensis DAUFPE 5622 (JJOH01000019.1).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number SIGI-HMM 797257 801732 4475 KDN76185.1 DF19_21910 797257 798648 -1 enterotoxin

797257 801732 4475 SIGI-HMM KDN76186.1 DF19_21915 798882 799103 1 hypothetical protein 1 797257 801732 4475 SIGI-HMM KDN76187.1 DF19_21920 799389 800591 1 cytochrome P450 797257 801732 4475 SIGI-HMM KDN76188.1 DF19_21925 800704 801732 1 3-oxoacyl-ACP synthase

157 Table S96. Predicted genomic islands in potential BGC from Streptomyces sp. E5N91 SAI-083 (NZ_RJKF01000001.1).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number 7571262 7575300 4038 IslandPick WP_123627566.1 EDC84_RS34290 7570858 7571283 1 CBS domain-containing protein sigma-70 family RNA polymerase 7571262 7575300 4038 IslandPick WP_123627567.1 EDC84_RS34295 7571341 7572360 1 sigma factor 1 7571262 7575300 4038 IslandPick WP_123627568.1 EDC84_RS34300 7572389 7573828 -1 FAD-dependent oxidoreductase polysaccharide pyruvyl 7571262 7575300 4038 IslandPick WP_123627569.1 EDC84_RS34305 7573843 7575081 -1 transferase 7571262 7575300 4038 IslandPick WP_123627570.1 EDC84_RS34310 7575238 7576188 1 TerC family protein 7585854 7591889 6035 IslandPick WP_123627580.1 EDC84_RS34370 7584925 7585890 1 pirin family protein 7585854 7591889 6035 IslandPick WP_123627581.1 EDC84_RS34375 7586121 7586444 1 transposase 7585854 7591889 6035 IslandPick WP_123627582.1 EDC84_RS34380 7586562 7588097 -1 alpha/beta hydrolase MerR family transcriptional 7585854 7591889 6035 IslandPick EDC84_RS34385 7588336 7589144 1 2 regulator 7585854 7591889 6035 IslandPick EDC84_RS34390 7589215 7589752 -1 IS701 family transposase methyltransferase domain- 7585854 7591889 6035 IslandPick WP_123627583.1 EDC84_RS34395 7589925 7590770 -1 containing protein acyltransferase domain- 7585854 7591889 6035 IslandPick WP_123627584.1 EDC84_RS34400 7590827 7594921 -1 containing protein pyridoxamine 5'-phosphate 7607165 7620916 13751 SIGI-HMM WP_123627586.1 EDC84_RS34410 7607165 7607695 1 oxidase family protein 3 SDR family NAD(P)-dependent 7607165 7620916 13751 SIGI-HMM WP_123627587.1 EDC84_RS34415 7607786 7620916 1 oxidoreductase SDR family NAD(P)-dependent 7607165 7620916 13751 SIGI-HMM WP_123627588.1 EDC84_RS34420 7620913 7639290 1 oxidoreductase 4 SIGI-HMM and SDR family NAD(P)-dependent 7638150 7646034 7884 WP_123627588.1 EDC84_RS34420 7620913 7639290 1 IslandPick oxidoreductase SIGI-HMM and 7638150 7646034 7884 WP_123627589.1 EDC84_RS34425 7639359 7640618 1 cytochrome P450 IslandPick SIGI-HMM and nuclear transport factor 2 family 7638150 7646034 7884 WP_123627590.1 EDC84_RS34430 7640615 7641016 1 IslandPick protein SIGI-HMM and 7638150 7646034 7884 WP_123627591.1 EDC84_RS34435 7641045 7641467 1 hypothetical protein IslandPick SIGI-HMM and NAD(P)-dependent 7638150 7646034 7884 WP_123627592.1 EDC84_RS34440 7641572 7642414 1 IslandPick oxidoreductase SIGI-HMM and nuclear transport factor 2 family 7638150 7646034 7884 WP_123627593.1 EDC84_RS34445 7642507 7642980 1 IslandPick protein SIGI-HMM and 7638150 7646034 7884 EDC84_RS34450 7643041 7644037 1 thioesterase IslandPick 7638150 7646034 7884 SIGI-HMM and WP_123627594.1 EDC84_RS34455 7644034 7645260 1 cytochrome P450 IslandPick

158 LLM class flavin-dependent 7638150 7646034 7884 IslandPick WP_123627595.1 EDC84_RS34460 7645913 7647094 1 oxidoreductase 7640615 7645260 4645 IslandPick WP_123627589.1 EDC84_RS34425 7639359 7640618 1 cytochrome P450 nuclear transport factor 2 family 7640615 7645260 4645 IslandPick WP_123627590.1 EDC84_RS34430 7640615 7641016 1 protein 7640615 7645260 4645 IslandPick WP_123627591.1 EDC84_RS34435 7641045 7641467 1 hypothetical protein NAD(P)-dependent 5 7640615 7645260 4645 IslandPick WP_123627592.1 EDC84_RS34440 7641572 7642414 1 oxidoreductase nuclear transport factor 2 family 7640615 7645260 4645 IslandPick WP_123627593.1 EDC84_RS34445 7642507 7642980 1 protein 7640615 7645260 4645 IslandPick EDC84_RS34450 7643041 7644037 1 thioesterase 7640615 7645260 4645 IslandPick WP_123627594.1 EDC84_RS34455 7644034 7645260 1 cytochrome P450 crotonyl-CoA 7649811 7657319 7508 IslandPick WP_123627597.1 EDC84_RS34475 7649079 7650443 1 carboxylase/reductase helix-turn-helix transcriptional 7649811 7657319 7508 IslandPick WP_123628731.1 EDC84_RS34480 7651139 7653916 1 regulator 7649811 7657319 7508 IslandPick EDC84_RS34485 7653975 7654518 -1 IS5/IS1182 family transposase 6 7649811 7657319 7508 IslandPick EDC84_RS34490 7654686 7655182 -1 ISAzo13 family transposase endo alpha-1,4 7649811 7657319 7508 IslandPick WP_123627598.1 EDC84_RS34495 7655281 7656108 -1 polygalactosaminidase 7649811 7657319 7508 IslandPick WP_123627599.1 EDC84_RS34500 7656863 7657768 1 class A beta-lactamase 7657633 7661732 4099 IslandPick WP_123627599.1 EDC84_RS34500 7656863 7657768 1 class A beta-lactamase 7657633 7661732 4099 IslandPick WP_123627600.1 EDC84_RS34505 7657765 7658109 1 transposase 7657633 7661732 4099 IslandPick WP_123627601.1 EDC84_RS34510 7658288 7658944 1 transposase NAD(P)-dependent alcohol 7657633 7661732 4099 IslandPick EDC84_RS34515 7659020 7659535 1 7 dehydrogenase 7657633 7661732 4099 IslandPick WP_123627602.1 EDC84_RS34520 7659701 7660423 1 alpha/beta hydrolase Gfo/Idh/MocA family 7657633 7661732 4099 IslandPick WP_123627603.1 EDC84_RS34525 7660579 7661721 1 oxidoreductase 7657633 7661732 4099 IslandPick EDC84_RS34530 7661725 7662434 -1 IS5/IS1182 family transposase

159 Table S97. Predicted genomic islands in potential BGC from Streptomyces olivaceus KLBMP 5084 (NZ_CP016795.1).

Island Island Island Length Method Gene name Locus Gene start Gene end Strand Product number start end 7944586 7951229 6643 Island Pick WP_070390064.1 BC342_RS34420 7943086 7945233 -1 MMPL family transporter TetR/AcrR family transcriptional 7944586 7951229 6643 Island Pick WP_037769115.1 BC342_RS34425 7945383 7945961 1 regulator 1 7944586 7951229 6643 Island Pick WP_079155146.1 BC342_RS34430 7946091 7949228 1 AAA family ATPase 7944586 7951229 6643 Island Pick WP_070390547.1 BC342_RS34435 7949283 7950356 -1 alcohol dehydrogenase 7944586 7951229 6643 Island Pick BC342_RS36420 7950486 7950671 1 siderophore-interacting protein 7944586 7951229 6643 Island Pick WP_079155147.1 BC342_RS34440 7950767 7952413 1 serine/threonine protein kinase SDR family NAD(P)-dependent 7979896 8005952 26056 SIGI-HMM BC342_RS34550 7979896 7991707 -1 oxidoreductase pyridoxamine 5'-phosphate oxidase 7979896 8005952 26056 SIGI-HMM WP_070390076.1 BC342_RS34555 7992082 7992603 1 2 family protein SDR family NAD(P)-dependent 7979896 8005952 26056 SIGI-HMM BC342_RS34560 7992716 8005952 1 oxidoreductase 7979896 8005952 26056 SIGI-HMM WP_070390077.1 BC342_RS34565 8005949 8024335 1 type I polyketide synthase 3 Island Pick, SIGI- HMM and 8023417 8032406 8989 WP_070390077.1 BC342_RS34565 8005949 8024335 1 type I polyketide synthase IslandPath- DIMOB Island Pick, SIGI- HMM and 8023417 8032406 8989 WP_037772595.1 BC342_RS34570 8024403 8025653 1 cytochrome P450 IslandPath- DIMOB Island Pick, SIGI- HMM and nuclear transport factor 2 family 8023417 8032406 8989 WP_070390078.1 BC342_RS34575 8025650 8026051 1 IslandPath- protein DIMOB Island Pick, SIGI- HMM and 8023417 8032406 8989 WP_037772597.1 BC342_RS34580 8026080 8026502 1 hypothetical protein IslandPath- DIMOB Island Pick, SIGI- HMM and 8023417 8032406 8989 WP_070390079.1 BC342_RS34585 8026607 8027449 1 NAD(P)-dependent oxidoreductase IslandPath- DIMOB Island Pick, SIGI- HMM and nuclear transport factor 2 family 8023417 8032406 8989 WP_037772601.1 BC342_RS34590 8027542 8028015 1 IslandPath- protein DIMOB Island Pick, SIGI- HMM and 8023417 8032406 8989 BC342_RS34595 8028096 8029092 1 thioesterase IslandPath- DIMOB 8023417 8032406 8989 Island Pick, SIGI- WP_078536178.1 BC342_RS34600 8029089 8030315 1 cytochrome P450

160 HMM and IslandPath- DIMOB Island Pick, SIGI- HMM and 8023417 8032406 8989 WP_123937984.1 BC342_RS36425 8030672 8030971 1 hypothetical protein IslandPath- DIMOB Island Pick, SIGI- HMM and LLM class flavin-dependent 8023417 8032406 8989 WP_031047091.1 BC342_RS34605 8030968 8032149 1 IslandPath- oxidoreductase DIMOB 4 Island Pick and 8025650 8172811 147161 IslandPath- WP_037772595.1 BC342_RS34570 8024403 8025653 1 cytochrome P450 DIMOB Island Pick and nuclear transport factor 2 family 8025650 8172811 147161 IslandPath- WP_070390078.1 BC342_RS34575 8025650 8026051 1 protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_037772597.1 BC342_RS34580 8026080 8026502 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390079.1 BC342_RS34585 8026607 8027449 1 NAD(P)-dependent oxidoreductase DIMOB Island Pick and nuclear transport factor 2 family 8025650 8172811 147161 IslandPath- WP_037772601.1 BC342_RS34590 8027542 8028015 1 protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34595 8028096 8029092 1 thioesterase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_078536178.1 BC342_RS34600 8029089 8030315 1 cytochrome P450 DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123937984.1 BC342_RS36425 8030672 8030971 1 hypothetical protein DIMOB Island Pick and LLM class flavin-dependent 8025650 8172811 147161 IslandPath- WP_031047091.1 BC342_RS34605 8030968 8032149 1 oxidoreductase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_031047088.1 BC342_RS34610 8032407 8033240 1 SDR family oxidoreductase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34615 8033502 8033938 1 hypothetical protein DIMOB 8025650 8172811 147161 Island Pick and WP_070390081.1 BC342_RS34620 8034080 8035444 1 crotonyl-CoA IslandPath- carboxylase/reductase DIMOB 8025650 8172811 147161 Island Pick and BC342_RS34625 8036200 8038975 1 helix-turn-helix transcriptional

161 IslandPath- regulator DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390082.1 BC342_RS34630 8039390 8040859 1 SAVED domain-containing protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390083.1 BC342_RS34635 8041289 8042275 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070387189.1 BC342_RS34640 8042389 8043714 1 ISL3 family transposase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070387188.1 BC342_RS34645 8045212 8046216 1 nucleotidyltransferase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070387187.1 BC342_RS34650 8046213 8047679 1 ThiF family adenylyltransferase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS36430 8047676 8048203 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS36435 8048298 8048636 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070387186.1 BC342_RS34655 8048719 8049045 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390084.1 BC342_RS34660 8049152 8050225 -1 ATP/GTP-binding protein DIMOB Island Pick and DDE-type 8025650 8172811 147161 IslandPath- WP_107405374.1 BC342_RS34665 8050225 8052336 -1 integrase/transposase/recombinase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390551.1 BC342_RS34670 8052618 8053325 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34675 8053536 8054456 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123937986.1 BC342_RS34680 8054469 8058035 -1 DNA-binding protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390552.1 BC342_RS34685 8058051 8059061 -1 AAA family ATPase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS36440 8059103 8061270 -1 transposase DIMOB 8025650 8172811 147161 Island Pick and WP_107405229.1 BC342_RS34700 8061267 8062250 -1 TnsA-like heteromeric transposase

162 IslandPath- endonuclease subunit DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155150.1 BC342_RS34705 8063902 8064456 -1 GNAT family N-acetyltransferase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390090.1 BC342_RS34710 8064890 8065825 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390554.1 BC342_RS34715 8066765 8067721 1 IS481 family transposase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155151.1 BC342_RS34720 8067652 8070510 1 serine/threonine protein kinase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390092.1 BC342_RS34725 8070565 8071245 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390093.1 BC342_RS34730 8071242 8073329 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390094.1 BC342_RS34735 8073379 8075418 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155152.1 BC342_RS34740 8075506 8077569 -1 helicase DIMOB Island Pick and CRISPR-associated endonuclease 8025650 8172811 147161 IslandPath- WP_070390555.1 BC342_RS34745 8078860 8081727 1 Cas3'' DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070389195.1 BC342_RS34750 8082043 8083308 -1 IS701 family transposase DIMOB Island Pick and type I-E CRISPR-associated 8025650 8172811 147161 IslandPath- WP_079155248.1 BC342_RS34755 8083539 8085026 1 protein Cse1/CasA DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_051159998.1 BC342_RS34760 8085026 8085670 1 hypothetical protein DIMOB Island Pick and type I-E CRISPR-associated 8025650 8172811 147161 IslandPath- WP_037772151.1 BC342_RS34765 8085888 8087051 1 protein Cas7/Cse4/CasC DIMOB Island Pick and type I-E CRISPR-associated 8025650 8172811 147161 IslandPath- WP_037772153.1 BC342_RS34770 8087048 8087857 1 protein Cas5/CasD DIMOB Island Pick and type I-E CRISPR-associated 8025650 8172811 147161 IslandPath- WP_070390095.1 BC342_RS34775 8087854 8088498 1 protein Cas6/Cse3/CasE DIMOB 8025650 8172811 147161 Island Pick and WP_063741599.1 BC342_RS34780 8088524 8090083 1 DDE-type

163 IslandPath- integrase/transposase/recombinase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123937988.1 BC342_RS34785 8090080 8090889 1 ATP-binding protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_037772156.1 BC342_RS34790 8091277 8092737 1 glycosyl hydrolase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_037772159.1 BC342_RS34795 8092741 8093640 -1 inorganic polyphosphate kinase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_037772162.1 BC342_RS34800 8093637 8094647 -1 SPFH/Band 7/PHB domain protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390096.1 BC342_RS34805 8095178 8096605 -1 hypothetical protein DIMOB Island Pick and winged helix-turn-helix domain- 8025650 8172811 147161 IslandPath- WP_070390097.1 BC342_RS34810 8097039 8098148 -1 containing protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390098.1 BC342_RS34815 8098145 8099434 -1 MFS transporter DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390099.1 BC342_RS34820 8099431 8100117 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34825 8100225 8101275 -1 YncE family protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155153.1 BC342_RS34830 8101345 8102037 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390101.1 BC342_RS34835 8102475 8102912 1 glyoxalase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390102.1 BC342_RS34840 8103305 8104564 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155154.1 BC342_RS34845 8104920 8108648 1 LamG domain-containing protein DIMOB Island Pick and RHS repeat-associated core 8025650 8172811 147161 IslandPath- BC342_RS34850 8108777 8114473 1 domain-containing protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155155.1 BC342_RS36455 8116473 8116682 1 DUF4291 family protein DIMOB 8025650 8172811 147161 Island Pick and WP_070390104.1 BC342_RS37465 8116689 8117315 -1 hypothetical protein

164 IslandPath- DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS36470 8117378 8118030 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34865 8118066 8118745 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS36475 8118783 8119242 1 DUF4291 family protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390106.1 BC342_RS34870 8119191 8119823 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390107.1 BC342_RS34875 8120019 8121062 -1 hypothetical protein DIMOB Island Pick and helix-turn-helix transcriptional 8025650 8172811 147161 IslandPath- WP_107405230.1 BC342_RS37255 8121154 8121495 1 regulator DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155158.1 BC342_RS36480 8122467 8122946 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_107405375.1 BC342_RS34900 8122943 8124439 1 ATP-dependent helicase DIMOB Island Pick and RHS repeat-associated core 8025650 8172811 147161 IslandPath- WP_070390113.1 BC342_RS34905 8125175 8128555 1 domain-containing protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34910 8129626 8129910 -1 IS630 family transposase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390114.1 BC342_RS34915 8130188 8130613 1 SRPBCC family protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS36485 8130942 8131115 -1 VOC family protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123937990.1 BC342_RS34925 8131592 8131951 -1 transposase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390556.1 BC342_RS34930 8132352 8133011 1 HNH endonuclease DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34935 8133117 8133317 1 hypothetical protein DIMOB 8025650 8172811 147161 Island Pick and WP_070390116.1 BC342_RS34940 8133499 8134689 -1 helix-turn-helix domain-containing

165 IslandPath- protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_037772213.1 BC342_RS34945 8135099 8135374 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123937992.1 BC342_RS37260 8135776 8136273 -1 CHAT domain-containing protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155249.1 BC342_RS34950 8136327 8136536 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123937994.1 BC342_RS34955 8136840 8137049 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_107405232.1 BC342_RS34960 8137262 8137801 1 hypothetical protein DIMOB Island Pick and DUF3761 domain-containing 8025650 8172811 147161 IslandPath- WP_070390119.1 BC342_RS34965 8138057 8138302 1 protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390120.1 BC342_RS34970 8138561 8139271 1 HNH endonuclease DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390121.1 BC342_RS34975 8139268 8139558 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390122.1 BC342_RS34980 8140230 8140733 1 lamin tail domain-containing protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34985 8140831 8141085 -1 HNH endonuclease DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34990 8141088 8141768 1 IS110 family transposase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS34995 8142090 8142375 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_107405233.1 BC342_RS35000 8142490 8145183 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS37270 8145315 8145419 -1 IS5/IS1182 family transposase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_037771683.1 BC342_RS35005 8145582 8146313 -1 MBL fold metallo-hydrolase DIMOB 8025650 8172811 147161 Island Pick and WP_031048538.1 BC342_RS35010 8146976 8147158 1 toxin-antitoxin system HicB family

166 IslandPath- antitoxin DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390126.1 BC342_RS35015 8147155 8147451 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155163.1 BC342_RS35020 8147526 8148077 1 kinase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390128.1 BC342_RS35030 8148466 8148660 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123937996.1 BC342_RS35035 8148684 8149055 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS36490 8149212 8149489 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390130.1 BC342_RS35040 8149778 8149999 1 hypothetical protein DIMOB Island Pick and helix-turn-helix domain-containing 8025650 8172811 147161 IslandPath- WP_070390131.1 BC342_RS35045 8150033 8150884 -1 protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390132.1 BC342_RS35050 8151064 8151864 1 oxidoreductase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_078536146.1 BC342_RS36495 8151914 8152225 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS35055 8152393 8153387 1 RacO protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_031031886.1 BC342_RS35060 8153390 8153809 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_037772147.1 BC342_RS35065 8153876 8154718 1 IS5 family transposase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_031031882.1 BC342_RS35070 8154769 8154987 -1 hypothetical protein DIMOB Island Pick and AraC family transcriptional 8025650 8172811 147161 IslandPath- WP_070390559.1 BC342_RS35075 8155244 8156233 -1 regulator DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390133.1 BC342_RS35080 8156265 8157179 1 alpha/beta hydrolase DIMOB 8025650 8172811 147161 Island Pick and BC342_RS36500 8157529 8157847 1 transposase

167 IslandPath- DIMOB Island Pick and SDR family NAD(P)-dependent 8025650 8172811 147161 IslandPath- WP_070390134.1 BC342_RS35085 8157992 8158960 1 oxidoreductase DIMOB Island Pick and TetR/AcrR family transcriptional 8025650 8172811 147161 IslandPath- BC342_RS37275 8158957 8159121 1 regulator DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390136.1 BC342_RS35095 8159586 8160857 1 M24 family metallopeptidase DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390137.1 BC342_RS35100 8160978 8161292 -1 transcriptional regulator DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123937998.1 BC342_RS37470 8161546 8161731 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- BC342_RS37280 8161733 8161858 -1 IS5/IS1182 family transposase DIMOB Island Pick and helix-turn-helix domain-containing 8025650 8172811 147161 IslandPath- WP_070390139.1 BC342_RS35110 8162200 8162796 1 protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390140.1 BC342_RS35115 8162823 8164934 1 hypothetical protein DIMOB Island Pick and helix-turn-helix domain containing 8025650 8172811 147161 IslandPath- WP_070390141.1 BC342_RS37285 8164934 8165653 1 protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390142.1 BC342_RS35125 8165937 8166293 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_079155166.1 BC342_RS36510 8166379 8166582 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_123938000.1 BC342_RS37475 8166679 8166867 -1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390144.1 BC342_RS35135 8167664 8170015 -1 XRE family transcriptional regulator DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390146.1 BC342_RS35145 8171127 8172332 1 hypothetical protein DIMOB Island Pick and 8025650 8172811 147161 IslandPath- WP_070390147.1 BC342_RS35150 8172329 8172811 1 hypothetical protein DIMOB 5 8026607 8030971 4364 SIGI-HMM WP_070390079.1 BC342_RS34585 8026607 8027449 1 NAD(P)-dependent oxidoreductase

168 nuclear transport factor 2 family 8026607 8030971 4364 SIGI-HMM WP_037772601.1 BC342_RS34590 8027542 8028015 1 protein 8026607 8030971 4364 SIGI-HMM BC342_RS34595 8028096 8029092 1 thioesterase 8026607 8030971 4364 SIGI-HMM WP_078536178.1 BC342_RS34600 8029089 8030315 1 cytochrome P450 8026607 8030971 4364 SIGI-HMM WP_123937984.1 BC342_RS36425 8030672 8030971 1 hypothetical protein LLM class flavin-dependent 8026607 8030971 4364 SIGI-HMM WP_031047091.1 BC342_RS34605 8030968 8032149 1 oxidoreductase 6 Island Pick and 8033093 8051282 18189 IslandPath- WP_031047088.1 BC342_RS34610 8032407 8033240 1 SDR family oxidoreductase DIMOB Island Pick and 8033093 8051282 18189 IslandPath- BC342_RS34615 8033502 8033938 1 hypothetical protein DIMOB Island Pick and crotonyl-CoA 8033093 8051282 18189 IslandPath- WP_070390081.1 BC342_RS34620 8034080 8035444 1 carboxylase/reductase DIMOB Island Pick and helix-turn-helix transcriptional 8033093 8051282 18189 IslandPath- BC342_RS34625 8036200 8038975 1 regulator DIMOB Island Pick and 8033093 8051282 18189 IslandPath- WP_070390082.1 BC342_RS34630 8039390 8040859 1 SAVED domain-containing protein DIMOB Island Pick and 8033093 8051282 18189 IslandPath- WP_070390083.1 BC342_RS34635 8041289 8042275 -1 hypothetical protein DIMOB Island Pick and 8033093 8051282 18189 IslandPath- WP_070387189.1 BC342_RS34640 8042389 8043714 1 ISL3 family transposase DIMOB Island Pick and 8033093 8051282 18189 IslandPath- WP_070387188.1 BC342_RS34645 8045212 8046216 1 nucleotidyltransferase DIMOB Island Pick and 8033093 8051282 18189 IslandPath- WP_070387187.1 BC342_RS34650 8046213 8047679 1 ThiF family adenylyltransferase DIMOB Island Pick and 8033093 8051282 18189 IslandPath- BC342_RS36430 8047676 8048203 1 hypothetical protein DIMOB Island Pick and 8033093 8051282 18189 IslandPath- BC342_RS36435 8048298 8048636 -1 hypothetical protein DIMOB Island Pick and 8033093 8051282 18189 IslandPath- WP_070387186.1 BC342_RS34655 8048719 8049045 -1 hypothetical protein DIMOB Island Pick and 8033093 8051282 18189 IslandPath- WP_070390084.1 BC342_RS34660 8049152 8050225 -1 ATP/GTP-binding protein DIMOB 8033093 8051282 18189 Island Pick and WP_107405374.1 BC342_RS34665 8050225 8052336 -1 DDE-type

169 IslandPath- integrase/transposase/recombinase DIMOB

170 Table S98. Predicted genomic islands in abyssomicin BGC from Streptomyces sp. Amel2xE9 (NZ_KB912999 and NZ_KB912981).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number 252366 258784 6418 SIGI-HMM WP_019985544.1 B065_RS38560 252366 252560 -1 hypothetical protein AfsR/SARP family 252366 258784 6418 SIGI-HMM WP_019985545.1 B065_RS0132280 252764 253537 1 transcriptional regulator 1 LuxR family transcriptional 252366 258784 6418 SIGI-HMM WP_019985546.1 B065_RS0132285 254243 257080 -1 regulator 252366 258784 6418 SIGI-HMM WP_019985547.1 B065_RS0132290 257354 258784 -1 MFS transporter 264101 271884 7783 SIGI-HMM WP_019985554.1 B065_RS0132325 264101 264307 -1 ferredoxin 264101 271884 7783 SIGI-HMM WP_027758724.1 B065_RS0132330 264313 265506 -1 cytochrome P450 ABC transporter ATP-binding 264101 271884 7783 SIGI-HMM WP_019985556.1 B065_RS0132335 266764 268431 -1 protein 2 264101 271884 7783 SIGI-HMM WP_106962190.1 B065_RS0132340 268428 269177 -1 ABC transporter permease 264101 271884 7783 SIGI-HMM WP_019985558.1 B065_RS0132345 269234 270235 -1 ABC transporter permease ABC transporter substrate- 264101 271884 7783 SIGI-HMM WP_027758725.1 B065_RS0132350 270220 271884 -1 binding protein

171 Table S99. Predicted genomic islands in potential abyssomicin BGC from Streptomyces incarnatus NRRL 8089 (CP011497).

Island Island start Island end Length Method Gene name Locus Gene start Gene end Strand Product number 395452 405212 9760 IslandPick AKJ08807.1 ABB07_01775 395560 396579 -1 luciferase 395452 405212 9760 IslandPick AKJ08808.1 ABB07_01780 396806 398005 1 cytochrome P450 395452 405212 9760 IslandPick AKJ08809.1 ABB07_01785 398038 398253 1 hypothetical protein 395452 405212 9760 IslandPick AKJ08810.1 ABB07_01790 398213 399256 -1 luciferase 1 395452 405212 9760 IslandPick AKJ08811.1 ABB07_01795 399560 401053 -1 MFS transporter 395452 405212 9760 IslandPick AKJ08812.1 ABB07_01800 401255 401860 1 TetR family transcriptional regulator 395452 405212 9760 IslandPick AKJ08813.1 ABB07_01805 401950 403293 1 nitrilotriacetate monooxygenase 395452 405212 9760 IslandPick AKJ08814.1 ABB07_01810 403277 404821 -1 hypothetical protein 395452 405212 9760 IslandPick AKJ08815.1 ABB07_01815 404898 405710 -1 hypothetical protein

172 Table S100. Predicted genomic islands in potential BGC from Micromonospora eburnea DSM 44814 (NZ_FMHY01000002.1).

Island Stran Island start Island end Length Method Gene name Locus Gene start Gene end Product number d LLM class F420-dependent 4701227 4709030 7803 IslandPick WP_091120850.1 GA0070604_RS20495 4700484 4701254 1 oxidoreductase 4701227 4709030 7803 IslandPick GA0070604_RS20500 4702315 4704202 1 hypothetical protein 4701227 4709030 7803 IslandPick GA0070604_RS20505 4703926 4705122 1 hypothetical protein 4701227 4709030 7803 IslandPick GA0070604_RS20510 4706074 4706952 1 hypothetical protein 4701227 4709030 7803 IslandPick GA0070604_RS20515 4707523 4708200 1 hypothetical protein 1 4701227 4709030 7803 IslandPick GA0070604_RS20520 4708213 4708737 1 hypothetical protein 4701227 4709030 7803 IslandPick GA0070604_RS20525 4708825 4709556 1 hypothetical protein 4709107 4714377 5270 IslandPick GA0070604_RS20525 4708825 4709556 1 hypothetical protein 4709107 4714377 5270 IslandPick GA0070604_RS20530 4709884 4710294 1 hypothetical protein 4709107 4714377 5270 IslandPick GA0070604_RS20535 4711306 4712406 1 hypothetical protein 4709107 4714377 5270 IslandPick GA0070604_RS20540 4712743 4713576 1 malonyl CoA-ACP transacylase 4709107 4714377 5270 IslandPick GA0070604_RS20545 4714183 4715653 1 hypothetical protein SDR family NAD(P)-dependent 4716822 4723967 7145 IslandPick WP_091120853.1 GA0070604_RS20550 4715710 4719729 1 oxidoreductase 4716822 4723967 7145 IslandPick WP_091120857.1 GA0070604_RS20555 4719968 4720201 1 hypothetical protein 4716822 4723967 7145 IslandPick WP_091120861.1 GA0070604_RS20560 4720423 4721184 -1 hypothetical protein 4716822 4723967 7145 IslandPick WP_091120868.1 GA0070604_RS20565 4721598 4722908 1 cytochrome P450 ABC transporter ATP-binding 4716822 4723967 7145 IslandPick WP_091120872.1 GA0070604_RS20570 4723627 4725360 1 2 protein 4735352 4739428 4076 IslandPick WP_091120887.1 GA0070604_RS20590 4730526 4735802 -1 type I polyketide synthase 4735352 4739428 4076 IslandPick WP_091120890.1 GA0070604_RS20595 4735878 4736921 -1 3-oxoacyl-ACP synthase 4735352 4739428 4076 IslandPick WP_091120894.1 GA0070604_RS20600 4736988 4738196 -1 cytochrome P450 4735352 4739428 4076 IslandPick WP_091120898.1 GA0070604_RS20605 4738235 4738834 -1 hypothetical protein 4735352 4739428 4076 IslandPick WP_091120901.1 GA0070604_RS20610 4739148 4744745 1 type I polyketide synthase 4759083 4764629 5546 IslandPick GA0070604_RS20625 4756912 4759682 1 hypothetical protein 4759083 4764629 5546 IslandPick GA0070604_RS20630 4759384 4760877 1 hypothetical protein 4759083 4764629 5546 IslandPick WP_091127296.1 GA0070604_RS20635 4760929 4761408 1 hypothetical protein 3 4759083 4764629 5546 IslandPick WP_091120909.1 GA0070604_RS20640 4761408 4762883 1 hypothetical protein 3-oxoacyl-ACP synthase III 4759083 4764629 5546 IslandPick WP_091120913.1 GA0070604_RS20645 4762944 4763975 1 family protein 4759083 4764629 5546 IslandPick GA0070604_RS20650 4764056 4765045 1 alpha/beta hydrolase AfsR/SARP family 4765348 4770810 5462 IslandPick WP_091120916.1 GA0070604_RS20655 4765165 4765938 -1 transcriptional regulator 4765348 4770810 5462 IslandPick WP_091120921.1 GA0070604_RS20660 4765935 4766723 -1 thioesterase 4 4765348 4770810 5462 IslandPick WP_091120924.1 GA0070604_RS20665 4767358 4769694 -1 AAA family ATPase 4765348 4770810 5462 IslandPick WP_091120927.1 GA0070604_RS20670 4770202 4770429 1 hypothetical protein lipopolysaccharide biosynthesis 4765348 4770810 5462 IslandPick WP_091120932.1 GA0070604_RS20675 4770588 4771895 1 protein RfbH

173 References

Abdalla, M. A., Yadav, P. P., Dittrich, B., Schüffler, A. & Laatsch, H. (2011). Ent-Homoabyssomicins A and B, two new spirotetronate metabolites from Streptomyces sp. Ank 210. Org Lett 13, 2156– 2159. Gottardi, E. M., Krawczyk, J. M., Von Suchodoletz, H., Schadt, S., Mühlenweg, A., Uguru, G. C., Pelzer, S., Fiedler, H. P., Bibb, M. J. & other authors. (2011). Abyssomicin biosynthesis: Formation of an unusual polyketide, antibiotic-feeding studies and genetic analysis. ChemBioChem 12, 1401–1410. Huang, P., Xie, F., Ren, B., Wang, Q., Wang, J., Wang, Q., Abdel-Mageed, W. M., Liu, M., Han, J. & other authors. (2016). Anti-MRSA and anti-TB metabolites from marine-derived Verrucosispora sp. MS100047. Appl Microbiol Biotechnol 100, 7437–7447. Igarashi, Y., Yu, L., Miyanaga, S., Fukuda, T., Saitoh, N., Sakurai, H., Saiki, I., Alonso-Vega, P. & Trujillo, M. E. (2010). Abyssomicin I, a modified polycyclic polyketide from Streptomyces sp. CHI39. J Nat Prod 73, 1943–1946. León, B., Navarro, G., Dickey, B. J., Stepan, G., Tsai, A., Jones, G. S., Morales, M. E., Barnes, T., Ahmadyar, S. & other authors. (2015). Abyssomicin 2 reactivates latent HIV-1 by a PKC- and HDACindependent mechanism. Org Lett 17, 262–265. Niu, X. M., Li, S. H., Görls, H., Schollmeyer, D., Hilliger, M., Grabley, S. & Sattler, I. (2007). Abyssomicin E, a highly functionalized polycyclic metabolite from Streptomyces species. Org Lett 9, 2437–2440. Riedlinger, J., Reicke, A., Zähner, H., Krismer, B., Bull, A. T., Maldonado, L. A., Ward, A. C., Goodfellow, M., Bister, B. & other authors. (2004). Abyssomicins, inhibitors of the para- aminobenzoic acid pathway produced by the marine Verrucosispora strain AB-18-032. J Antibiot (Tokyo) 57, 271–279. Song, Y., Li, Q., Qin, F., Sun, C., Liang, H., Wei, X., Wong, N. K., Ye, L., Zhang, Y. & other authors. (2017). Neoabyssomicins A–C, polycyclic macrolactones from the deep-sea derived Streptomyces koyangensis SCSIO 5802. Tetrahedron 73, 5366–5372. Wang, Q., Song, F., Xiao, X., Huang, P., Li, L., Monte, A., Abdel-Mageed, W. M., Wang, J., Guo, H. & other authors. (2013). Abyssomicins from the South China Sea deep-sea sediment Verrucosispora sp.: Natural thioether michael addition adducts as antitubercular prodrugs. Angew Chemie - Int Ed 52, 1231–1234. Wang, X., Elshahawi, S. I., Cai, W., Zhang, Y., Ponomareva, L. V., Chen, X., Copley, G. C., Hower, J. C., Zhan, C.-G. & other authors. (2017). Bi- and tetracyclic spirotetronates from the coal mine fire isolate Streptomyces sp. LC-6-2. J Nat Prod 2, acs.jnatprod.7b00108.